WO2000001383A1

WO2000001383A1 - Angiogenesis inhibitors

Info

Publication number: WO2000001383A1
Application number: PCT/US1999/015252
Authority: WO
Inventors: Kyriacos C. Nicolaou; John Trujillo; Kelly Chibale; Bernd Jandeleit; Simon Goodman
Original assignee: The Scripps Research Institute
Priority date: 1998-07-06
Filing date: 1999-07-06
Publication date: 2000-01-13
Also published as: HUP0104509A2; HUP0104509A3; KR20010079497A; BR9911885A; JP2002519377A; SK242001A3; ID28125A; PL345574A1; EP1094812A4; CA2336774A1; CN1308534A; NO20010085D0; ZA200007405B; AU4862599A; NO20010085L; EP1094812A1

Abstract

RGD mimetics which combine a nitroaryl moiety with an arylether/α-aminoacid/guanidine framework exhibit activity as antagonists toward various integrins and as inhibitors of angiogenesis.

Description

ANGIOGENESIS INHIBITORS

SPECIFICATION

Technical Field:

The present invention relates to nonpeptide compounds having RGD mimetic activity and to the synthesis and biological activity of nonpeptide compounds having RGD mimetic activity. More particularly, the present invention relates to nitroaryl based nonpeptide RGD mimetics and to their synthesis and biological activity.

Background :

The integrins are a class of extracellular proteins that facilitate cell-cell and cell-matrix adhesion (Cheresh, D.A.; Mecham, R.P. Eds.; Academic Press: New York, 1994; Stromblad, S.; Cheresh, D.A. Chem. Biol . 1996, 3, 881) These important biological targets are membrane bound, heterodimeric glycoproteins made up of an -subunit and a smaller β-subunit. The relative affinity and specificity for ligand binding is determined by the unique combination of the different α- and β- subunits. Of the members of this family of receptors, α_IIbβ₃, a_{5 l r} Oi_vβ₃, and α_vβ₅ are the most studied. A number of known natural ligands to these integrins, such as fibronectin (binds to ₅β₁) , fibrinogen (binds to α_IIbβ₃) and vitronectin (binds to Q!_vβ₃) , contain the key peptide sequence Arg-Gly-Asp (RGD) within their native sequence, which is recognized by most integrins. The α_IIbβ₃ integrin was shown to be an excellent target for the inhibition of platelet aggregation and several groups have already disclosed the design and synthesis of potent binders with peptide and nonpeptidal structures (Ojima et al . Bioorg. Med. Chem., 1995, 337; Engleman et al . Ann. Rep. Med. Chem. 1996, 31, 191).

Within the context of angiogenesis , the functions of <3_vβ₃ and α_vβ₅ have been shown to be vital. Cheresh and coworkers have shown that in vivo inhibition of binding of these integrins to their RGD-containing ligands by antibodies or cyclic peptides interferes with angiogenesis and induces tumor regression (Brooks et al . Science 1994 et al . Rosenfeld et al . Cell 1994, 79, 1157). In addition to its relevance to angiogenesis, CX._vβ₃ has also been known to play a role in mediating adhesion of osteoclasts to the bone matrix and in the migration of vascular smooth muscle cells.

Antagonists of X_vβ₃ are, therefore, envisioned as potential therapeutic agents for the treatment of numerous disease states such as diabetic retinopathy, cancer, osteoporosis and restenosis (Van der Pluijm et al . Bone Mineral Res. 1994, 9, 1021; Helfrich et al . J. Bone Mineral Res. 1992, 7, 335; Horton et al . Ex . Cell Res. 1991, 195, 368; Robey et al . Ann. Rep. Med. Chem. 1993, 28, 227; Choi et al. Surgery 1994, 19, 125; Matsuno et al . Circulation 1994, 90, 2203; Hammes et al . Nature Med. 1996, 2, 529; Friedlander et al. Proc. Natl. Acad. Sci., USA 1996, 93, 9764.

The first small molecule antagonists of 0C_vβ₃ were reported by Kessler et al . (e.g. 1, Figure 1; Gurrath et al .

Eur. J. Biochem. 1992, 210, 911; Muller et al . Angew. Chem.

Int. Ed. Engl. 1992, 31, 326; Aumailley et al . FEBS Lett.

1991, 291, 50; Pfaff et al . J. Biol . Chem. 1994, 269, 20233; Haubner et al . J. Am. Chem. Soc . 1996, 118, 7461).

Subsequently, groups from Dupont-Merck (e.g. 2, Figure 1) and

SmithKline Beecham (SKB) (e.g. 3, Figure 1) published their results in the field. In addition, other RGD containing cyclic peptides 4 and 5 (Figure 1) were synthesized and shown to be active by Burgess et al . and Goodman et al . respectively

(Bach et al . J. Am. Chem. Soc. 1996, 118, 293; Peishoff et al .

J. Med. Chem. 1992, 35, 3962; Burgess et al . J. Med. Chem.

1996, 39, 4520; Tran et al . Bioorg. Med. Chem. Lett. 1997, 7,

997) .

More recently a number of groups reported their results with high affinity ligands for CX_vβ₃ possessing structures significantly deviating from classical peptide frameworks (e.g. 6-9, Figure 2) . These structures contain a central scaffold (e.g. benzene, benzodiazepine-type or urea backbone) onto which appendages carrying carboxylate and guanidino groups are attached (Duggan et al . Abstracts of Papers, 211th ACS National Meeting, New Orleans, LA, March 24-28, 1996; American Chemical Society: Washington, DC, 1996, MEDI 234; Keenan et al . J. Med. Chem. 1997, 40, 2289; Corbett et al . Bioorg. Med. Chem. Lett. 1997, 7, 1371; Gadek et al . Abstracts of Papers, 211th ACS National Meeting, New Orleans, LA, March 24-28, 1996; American Chemical Society: Washington, DC, 1996, MEDI 235; Hirschmann et al . J. Am. Chem. Soc. 1996, 115, 12550) .

What is needed are synthetically accessable RGD mimetics which posses stability in vivo with high activity and selectivity against various integrin targets. Furthermore, what is needed is an efficient and general method to produce such compounds .

Summary of the Invention :

The invention is directed to the design, chemical synthesis and biological evaluation of a series of nitroaryl- based RGD mimetics. More particularly, the invention is directed to compounds which combine a novel nitroaryl system with arylether/α-aminoacid/guanidine frameworks of the type disclosed in U.S. Patent No. 5,741,796, issued April 21, 1998, incorporated herein by reference, i.e., the "Merck compounds".

One aspect of the invention is directed to an RGD mimetic represented by the following structure:

In the above structure, R¹ is selected from the following radical :

Here, X is a diradical selected from sulfur, -NH- and oxygen. R² is a radical selected from -C0₂t-Butyl, -CO-Aryl and -S0₂- Aryl . Preferred Aryls include phenyl , 1-naphthyl, and 2- naphthyl . A preferred R² radical is -S0₂-Aryl. A preferred RGD mimetic is represented by the following structure:

Other preferred RGD mimetics are represented by the following structures :

Another aspect of the invention is directed to a method for producing the above RGD mimetics. Firstly, a nitroaryl precursor is provided having a fluoride group covalently attached to the nitroaryl ring represented by the following structure:

In the above structure, R₃ is an acid protecting group. Then, the fluoride group is displaced with a nucleophile having a protected guanidine group using nucleophilic aromatic substitution for producing a protected RGD mimetic. Finally, the protected RGD mimetic is deprotected with an acid for producing the RDG mimetic.

Another aspect of the invention is directed to an RGD mimetic represented by the following structure:

In the above structure, R² is a radical selected from a group consisting of -C0₂t-Butyl, and -S0₂-Aryl. Preferred Aryls include phenyl, 1-naphthyl, and 2-naphthyl.

The above RGD mimetics were tested against a variety of integrins (α_vβ₃, o_IIbβ₃ and α_vβ₅) for their ability to inhibit cell adhesion and in order to determine their binding selectivity. Selected compounds were also tested for their ability to inhibit angiogenesis in vivo in the CAM (chick chorioallantoic membrane) assay. All compounds were verified to have inhibitory activity and selectivity against the above targets, consistant with their activity as inhibitors of angiogenesis

Another aspect of the invention is directed to a process for differentially inhibiting α_llbβ₃ mediated cell adhesion over α_vβ₃ mediated cell adhesion. Cells that express α_llbβ₃ are contacted with a solution containing selected RGD mimetics. The solution has a concentration of such RGD mimetics sufficient for inhibiting α_llbβ₃ mediated cell adhesion. As a result, α_llbβ₃ mediated cell adhesion is inhibited at least approximately 100 fold more than _vβ₃ mediated cell adhesion. Preferred RGD mimetics employable for this aspect of the invention are as follows:

Description of Figures :

Figure 1 illustrates selected structures of α_vβ₃ antagonists based on the RGD peptide sequence.

Figure 2 illustrates selected nonpeptide RGD mimetics with high affinity for Oi_vβ₃.

Figure 3 illustrates targeted nitroaryl ethers (10-21) as RGD mimetics and benzimidazole 22.

Figure 4 illustrates general structures of nitroarylether RGD mimetics and retrosynthetic analysis.

Figure 5 illustrates synthesis of amino esters 26, 29a and 29b with the following Reagents and condi tions : (a) 1.1 equivalents of Boc₂0, 1.0 equivalent of Na₂C0₃, 1,4-dioxane, H₂0, 25°C, 88%; (b) i ) 20% aqueous solution of Cs₂C0₃, H20:Me0H (1:2.5), 25°C, 4 hours, 100%, ii ) 1.1 equivalents of BnBr, DMF, 25°C, 14 hours, 88%; (c) 1.5 equivalents of Phi (OCOCF ₃) ₂, DMF:H₂0 (1:1), 2.0 equivalents of pyridine, 25°C, 3.5 hours, 41%; (d) 1.1 equivalents of ArS0₂Cl, 2.25 equivalents of NaOH, dioxane:H₂0 (1:2), 0 to 25°C, 3 hours, [71% for 27a, 66% for 27b]; (e) 1.3 equivalents of Br₂, 9.2 equivalents of NaOH, H₂ ^'0, 0 to 90°C, [75% for 28a, 81% for 28b]; (f) isobutylene, 2.8 equivalents of cone. H₂S0₄, DME, -78 to 25°C, 48 hours, [55% for 29a, 51% for 29b] . DME = dimethoxyethane; DMF = dimethylformamide; Ph = phenyl ; 2-naphthyl.

Figure 6 illustrates the synthesis of compounds 10 - 13 with the following Reagents and condi tions : (a) 5.0 equivalents of MeC(OMe)₃, PhMe, 80°C, 8 hours, 98%; (b) 1.1 equivalents of N₃ (CH₂) ₂OTBS, 0.1 equivalents of TBAF, 4 A MS, DMF, 25°C, 4 hours, 73%; (c) 2.0 equivalents of LiOH«H₂0, 3:1 dioxane:H20 (3:1), 25°C, 4 hours, 99%; (d) 1.0 equivalent of DCC, 0.2 equivalents of 4-DMAP, CH₂C1₂, 25°C, 4 hours, 82%; (e) 50% TFA in CH₂C1₂, 25°C, 2 hours, 84%; (f) 1.1 equivalents of PhS0₂Cl or l-NaphS0₂Cl, 1.3 equivalents of i-Pr2NEt, CH₂C1₂, 25°C,4 hours, 38a (78%), or 38b (57%); (g) 2.0 equivalents of Ph₃P, 44 equivalents of H₂0, THF, 25°C, 12 hours, 80%, ca . 1:1 of 35a:35b; 80%, ca . 1:1 of 39a:41a; 81%, ca. 1:1 of 39b:41b; (h) 2.0 equivalents of LiOH»H₂0, THF : H₂0 (3:1), 25°C, 4 hours, 93-99% for 36ab, 40ab, 42a; (i) 1.1 equivalents of 1 H- pyrazole-l-carboxamidine»HCl, 1.1 equivalents of i-Pr₂NEt, DMF, 25°C, 16 hours, 13-15% for 10, 11, 13; 50°C, 16 hours, 5% for 12, after RP-HPLC. TFA = trifluoroacetic acid; TBAF = tetra-π-butylammonium fluoride; DCC = 1,3- dicyclohexylcarbodiimide .

Figure 7 illustrates the snthesis of guanidine derivatives 51 - 56 with the following Reagents and condi tions : (a) 1.0 equivalent of BtBMTP, 2.0 equivalents of Et₃N, 1.0 equivalent of HgCl₂, DMF, 25°C, 4 hours, 98%; (b) 1.0 equivalent of BtBMTP, DMF, 25°C, 14 hours, 95%; (c) 1.0 equivalent of BtBCT, DMF, 25°C, 14 hours, 60%; (d) 0.2 equivalents of BtBMTP, 0.4 equivalents of Et₃N, 0.2 equivalents of HgCl₂, DMF, 25°C, 4 hours, 51%; (e) 0.66 equivalents of o-NH₂C₆H₄NH₂, 5.5 N aqueous HCl, reflux, 24 hours, 73%; (f) 1.0 equivalent of DmPD»HBr, iPr₂NEt, DMF, 25°C, 11 hours, 51%. Boc = tert-butoxycarbonyl ; BtBCT = N, N' - Bis- tert-butoxycarbonylthiourea; BtBMTP = 1 , 3-bis ( ert- butoxycarbonyl) -2-methyl-2- thiopseudourea; DmPD «HBr = 2- (3, 5- dimethylpyrazolyl) -4 , 5-dehydroimidazole hydrobromide .

Figure 8 illustrates the synthesis of compounds 11 and 14-19 with the following reagents and conditions: (a) 1.2 equivalents of (C0C1)₂, PhH, DMF, 0°C, 6 hours, 99%; (b) 1.0 equivalent of 29a or 29b, 1.2 equivalents of Et₃N, CH₂C1₂, 0°C, 2 hours, 58 (98%), or 59 (96%); (c) for 60: 2.2 equivalents of NaH, 2.2 equivalents of 51, DMF, 25°C, 8 hours, 66%; for 63:

4.0 equivalents of NaH, 1.2 equivalents of 51, DMF, 25°C, 4 hours, 69%; (d) 1.1 equivalents of 53, DMF, 25°C, 4 hours, 73%; for 64: 1.9 equivalents of 53, NMP, 25°C, 99%; (e) for 65: 2.2 equivalents of NaH, 2.5 equivalents of 54, DMF, 25°C, 12 hours, 23%; (f) 1.1 equivalents of 52, DMF, 25°C, 6 hours, 83%; for 66: 2.0 equivalents of 52, DMF, 25°C, 20 hours, 99%; (g) 50% TFA in CH₂C1₂, 25°C, 30 min, 90-99% for 11, 14-19 after RP-HPLC . Boc = tert-butoxycarbonyl; TFA = trifluoroacetic acid; NMP = N-methyl-2-pyrrolidinone; DMF = dimethylformamide .

Figure 9 illustrates the synthesis of compounds 20 and 21 witht the following Reagents and condi tions : (a) 1.0 equivalent of 55, 2.2 equivalents of Et₃N, DMF, 25°C, 16 hours, 92%; (b) 50% TFA in CH₂C1₂, 25°C, 4 hours, 97%; (c) 1.0 equivalent of 56, 2.2 equivalents of Et₃N, DMF, 12 hours, 120%(crude yield); (d) 50% TFA in CH₂C1₂, 25°C, 4 hours, 83% after RP-HPLC; TFA = trifluoroacetic acid; DMF = dimethylformamide .

Figure 10 illustrates the synthesis of compound 22 with the following Reagents and condi tions : (a) NH₃, DMF, 25°C, 5 hours, 93%; (b) 10% Pd/C, H₂, MeOH, 25°C, 8 hours, 90%; (c)

1.1 equivalent of PhNCS, EtOH, 14 hours, 69%; (d) 1.0 equivalent of HgCl₂, 1.0 equivalent of Et3N, DMF, 4 hours, 81%; (e) 50% TFA in CH2C12, 30 min, 88% yield, after RP-HPLC. TFA = trifluroacetic acid; DMF = dimethylformamide.

Figure 11 shows a compilation of data which indicates the effect of nitroaryl ethers on RGD-dependent ligand interaction with integrins. The concentration necessary for half-maximal inhibition of ligand binding (IC₅₀) is shown. The peptide GRGDSPK and compound 1 were included for reference. The data have been sorted by IC₅₀ values (from low to high) on α_vβ₃. The 'cQ' value shows the activity of the NPE relative to the activity of compound 1. The >', shows that the IC ₅₀ had not been reached at the maximum concentration tested, 10 μM.

Figure 12 shows a compilation of data which indicates the effect of nitroaryl ethers on RGD-dependent cell adhesion to immobilized ligands. The concentration necessary for half- maximal inhibition of ligand binding (IC₅₀) is shown. 25000 cells were allowed to adhere to immobilized ligands in the presence of the nitroaryl ethers as described herein. The concentration resulting in half-maximal inhibition of cell adhesion (IC₅₀) is shown. The data have been sorted by IC ₅₀ (from low to high) on α_vβ₃ mediated adhesion of M21 cells.

Detailed Description:

Example 1: Design, Synthesis and Biological Evaluation of Nonpeptide Itegrin Antagonists:

In this example we describe the design, chemical synthesis and biological evaluation of a series of nitroaryl- based RGD mimetics. Figure 3 shows the targeted compounds (10-22) . Amongst the considerations that led to their design were : (a) the Merck findings pointing to the importance of the guanidine/aryl sulfonamide functionalities (Duggan et al . Abstracts of Papers, 211th ACS National Meeting, New Orleans, LA, March 24-28, 1996; American Chemical Society: Washington, DC, 1996, MEDI 234); and (b) the facile entry into such structures from o-nitro-arylfluorides as shown in Figure 4. The designed molecules fall within the general structure I (Figure 4) which can be derived by coupling the central nitrofluoroaromatic system II with fragments III (nucleophile) and IV (aminoacid component) .

For the synthesis of compounds 10-22 (Figure 3), the amino acid derivatives 26, 29a and 29b were required. These intermediates were obtained from L-asparagine (23) as outlined in Figure 5. Thus, conversion of 23 to its Boc derivative (24, 88%) under standard conditions was followed by benzyl ester formation (Cs₂C0₃-BnBr) to afford 25 (88% yield) . Reduction of the primary amide with PhI(0C0CF₃)₂ furnished derivative 26 in 41% yield. The sulfonamides 29a and 29b were prepared by sulfonylation of the amino group to afford 27a, followed by Hoffmann rearrangement and esterification of the resulting aminoacids (28a and 28b) with isobutylene (Figure 5) .

Figure 6 summarizes the initial approach to compounds 10- 13. Thus, 4-fluoro-o-nitrobenzoic acid (30) was converted to its methyl ester (31, 98%) by treatment with trimethylorthoacetate at 80°C, and thence reacted with N₃(CH₂)₂OTBS in DMF in the presence of catalytic amounts of TBAF resulting in the formation of compound 32 (73%; yields are unoptimized) . Saponification of 32 (LiOH, 99% yield) furnished carboxylic acid 33 which was condensed with building block 26 in the presence of DCC and 4-DMAP to give key intermedate 34 (82% yield). For the synthesis of 10, compound 34 was reduced with Ph₃P in the presence of H₂0, to afford amine 35a, together with the rearranged product 35b (80% combined yield) in which the side chain heteratoms have interchanged positions (via an internal nucleophilic attack, see structure 35a) . On standing at ambient temperature, primary amine 35a underwent quantitative conversion to primary alcohol 36b. However, it was possible to rapidly manipulate the compound through basic hydrolysis (LiOH) and guanylation (lH-pyrazole-1-carboxamidine •HCl) and obtain the targeted compound 10 albeit in low yield (15% after RP-HPLC purification) .

For the synthesis of the sulfonamide compounds 11-13, the common intermediate 34 was deprotected (TFA, 84%) and the liberated amine (37) was reacted with the appropiate sulfonyl chloride to afford compounds 38a (78 %) and 38b (57 %) .

Reduction of the azide functionality in 38a and 38b with Ph ₃P- H₂0, again resulted in a mixture of the corresponding primary amine (39a and 39b) and its rearranged primary alcohol (41a and 41b) in 80% total yield. Basic hydrolysis of 39a and 39b resulted in the formation of the corresponding carboxylic acids (40a and 40b, 93-99% yield) , guanylation of which as described above furnished the desired compounds 11 and 13 (13- 15% yield) respectively. Similarly, hydrolysis of 41a (LiOH, 96% yield) followed by guanylation furnished compound 12 in low yield, via compound 42a.

The rearrangement observed during the reduction of the side chain azido group led us to explore an alternative strategy for the construction of the targeted nitroaryl ether compounds. According to the new plan, a nucleophilic species containing a fully protected guanidine moiety was to be employed in the displacement of the fluoride from the central nitroaryl system. To this end the nucleophiles 51-56 (Poss et al. Tetrahedron Lett. 1992, 33, 5933; Iwanowicz et al . Synth. Commun. 1993, 23, 1443; Cherkaoui et al . Bull. Soc. Chim. Fr . 1991, 255) were prepared from readily available starting materials and by standard chemistry as outlined in Figure 7. The incorporation of these fragments into the mainframe of the molecule via nucleophilic aromatic substitution, and the synthesis of the final targets are shown in Figure 8 (11, 14- 19) and Figure 9 (21 and 22) . Thus, the acid chloride 57 (derived from carboxylic acid 30) was coupled with amines 29a and 29b in the presence of Et₃N to afford amides 58 (98%) and 59 (99%) respectively. Coupling of 58 with nucleophile 51 was effected in the presence of NaH in DMF to afford product 60 in 66% yield. Similarly 63 was obtained by coupling 59 with 51 (69% yield) . The amino compounds 61 and 64 were obtained from 58 and 59 in 73 and 99% yield respectively, by reaction with amine 53 in DMF at ambient temperature. Thioether 62 was obtained by exposure of 58 to thiol 54 and NaH (DMF, 25°C, 23% yield) . Treatment of componds 60-64 with TFA in CH₂C1₂ at room temperature resulted in concomitant deprotection of both the guanidine and carboxyl groups in excellent yield (90-99%, after RP-HPLC purification) . The piperazine compounds 16 and 19 were prepared in a similar fashion from 58 and 59 respectively by first displacing the fluoride with nucleophile 52, followed by TFA-induced deprotection of the resulting derivatives 65 and 66 as summarized in Figure 8.

The synthesis of compounds 20 and 21 is shown in Figure 9. Thus, reaction of 58 with 55 in the presence of Et ₃N at 25°C in DMF resulted in the formation of compound 67 (92% yield) which was exposed to TFA:CH₂C1₂ (1:1) at 25°C to afford targeted benzimidazole 20 (97% yield) . In a similar fashion, compound 21 was prepared via the intermediacy of 68 by reaction of 58 with 56 (Et₃N, DMF, 25°C, 94%), followed by deprotection (83% after RP-HPLC purification).

Finally, the preparation of compound 22 is shown in Figure 10. Thus, key intermediate 57 was reacted with ammonia in DMF to afford nitroaniline 69 in 93% yield. Reduction of 69 with H₂ in the presence of 10% Pd/C catalyst in MeOH led to 1,2 diamine 70 (90%), which reacted with phenylisothiocyanate in EtOH to afford thiourea 71 (69% yield) . Treatment of 71 with HgCl₂ and Et₃N in DMF at ambient temperature gave guanidine 72 in 81% yield. Cleavage of the tert-butyl ester in 72 with TFA in CH₂C1₂ then led to the targeted compound 22 (80% yield, after RP-HPLC purification) .

EXPERIMENTAL PROTOCALS

General :

All reactions were carried out under an argon atmosphere with dry, freshly distilled solvents under anhydrous conditions, unless otherwise noted. Tetrahydrofuran (THF) and diethyl ether (ether) were distilled from sodium-benzophenone, and methylene chloride (CH₂C1₂) , benzene (PhH) , and toluene from calcium hydride. Anhydrous solvents were also obtained by passing them through commercially available activated alumina columns . Yields refer to chromatographically and spectroscopically ( ^^"H NMR) homogeneous materials, unless otherwise stated. All solutions used in workup procedures were saturated unless otherwise noted. All reagents were purchased at highest commercial quality and used without further purification unless otherwise stated.

All reactions were monitored by thin-layer chromatography carried out on 0.25 mm E. Merck silica gel plates (60F-254) using UV light as visualizing agent and 7% ethanolic phosphomolybdic acid or p-anisaldehyde solution and heat as developing agents. E. Merck silica gel (60, particle size 0.040-0.063 mm) was used for flash column chromatography. Preparative thin-layer chromatography separations were carried out on 0.25, 0.50 or 1 mm E. Merck silica gel plates (60F-

254) . Reverse phase HPLC was performed on a Waters Model 600E HPLC instrument utilizing a Vydac 218TP1022 column with detection at 254 nm using a 90:10 E 40:60 H₂0:CH₃CN + 0.1% TFA gradient over 40 minutes.

NMR spectra were recorded on Bruker DRX-600, AMX-500, AMX-400 or AC-250 instruments and calibrated using residual undeuterated solvent as an internal reference. The following abbreviations were used to explain the multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; m, multiples- band, several overlapping signals; b, broad. IR spectra were recorded on a Perkin-Elmer 1600 series FT-IR spectrometer. High resolution mass spectra (HRMS) were recorded on a VG ZAB- ZSE mass spectrometer under fast atom bombardment (FAB) conditions. Electrospray mass spectra were recorded on a Perkin Elmer Science API III mass spectrometer.

Synthesis of Amino Acid Derivative 25 as shown in Figure 5.

Compound 25: To a solution of t-butoxy-carbonyl- ( L) - asparagine 24 (12.6 g, 50 mol; Aldrich) in MeOH (200 mL) was added water (20 mL) . The solution was neutralized with a 20% aqueous solution of Cs₂C0₃ (57 mL) and then evaporated to dryness. The resulting residue was taken up in DMF (50 mL) and then azeotropically dried by evaporation to dryness. The cesium salt was then taken up in DMF (125 mL) followed by addition of benzyl bromide (6.5 mL, 55 mmol) . The mixture was stirred at room temperature for 6 hours, evaporated to dryness and the residue triturated with water (500 mL) . The solid was dissolved in ethyl acetate (150 mL) and the organic phase was washed with water (75 mL) , dried over Na₂S0₄ and the solvent was removed under reduced pressure. The crude ester was recrystallized from ethyl acetate/hexane to give 25 (15.1 g, 88 %) as a colorless solid. IR (KBr) : n_max3401, 3349, 3204, 2982, 2935, 1741, 1688, 1657, 1524, 1293, 1169, 1055 cm^"1; Η NMR (500 MHz, CDCl₃): d 7.36-7.32 (m, 5 hours, Ph) , 5.73 (d, J = 8.5 Hz, 1 H, NHC0₂), 5.59 (bs, 1 H, CONHff) , 5.40 (bs, 1 H, CONHH) , 5.20 (d, J^" = 12.5 Hz, 1 H, CHHPh) , 5.17 (d, J^" = 12.5 Hz, 1 H, CHHPh), 4.56 (ddd, J = 4.0 , 5.0, 8.5 Hz, 1 H, CHCH₂) , 2.95 (dd, J = 5.0, 16.5 Hz, 1 H, CHCHH), 2.76 (dd, J = 4.0, 16.5 Hz, 1 H, CHCHH), 1.42 (s, 9 H, ^fcBu) ; ¹³C NMR (150 MHz, CDClj) : d 171.9, 171.2, 155.7, 135.4, 128.5, 128.3, 128.2, 80.1, 67.4, 50.3, 37.4, 28.3; FAB-HRMS (M+Na⁺) calcd 345.1426 , found 345.1421.

Synthesis of compound 26 as illustrated in Figure 5 : To a stirred solution of bis [ trifluoroacetoxy] phenyl iodine (2.0 g, 4.7 mmol) in DMF:H₂0 (24 mL, 1:1, v/v) compound 25 (1.0 gram, 3.1 mmol) was added at room temperature. After 15 min, pyridine (0.5 mL, 6.2 mmol) was added and stirring was continued for 3 hours . The solvent was removed under reduced pressure and the residue dissolved in water (30 mL) . The solution was washed with ether and the aqueous layer was basified with 1 N NaOH and extracted with dichloromethane. The solvent was removed under reduced pressure to give an oily residue. Purification by flash column chromatography (10 % MeOH in CH₂C1₂) gave amine 26 as a yellow oil (0.37 grams, 41%). R_f = 0.11 (2.5% methanol in ethyl acetate); IR (thin film): n„3366, 3313, 3064, 2979, 2934, 1688, 1518, 1501, 1456, 1393, 1368, 1324, 1254, 1204, 1166, 1055, 1002, 838, 800, 743, 692 cm^"1; Η NMR (500 MHz, CDC1₃) : d 7.36-7.28 (m, 5 H, Ph) , 6.36 (bm, 2 H, NH₂) , 6.06 (d, J = 7.5 Hz, 1 H, NHC0₂) , 5.18 (d, J^" = 12.0 Hz, 1 H, CHHPh), 5.13 (d, J = 12.0 Hz, 1 H, CHHPh), 4.52-4.43 (bm, 1 H, CHCH₂) , 3.35 (bdd, J = 12.5 Hz, 1 H, CHCHH), 3.24 (bdd, J = 6.5, 12.5 Hz, 1 H, CHCHH), 1.32 (s, 9 H, ^fcBu) ; ¹³C NMR (125 MHz, CDC1₃): d 170.0, 155.9, 134.8, 128.5, 128.4, 128.3, 80.6, 67.7, 52.9, 41.6, 28.0; FAB-HRMS (M+H⁺) calcd 295.1658, found 295.1650.

Synthesis of compound 27a as illustrated in Figure 5. To a solution of ( L) -asparagine (23) (10.00 grams, 75.7 mmol) in H₂0:dioxane (50 mL:50 mL) was added NaOH (3.40 grams, 85.0 mmol) at 0°C. After 15 min at 0°C, phenylsulfonylchloride (10.6 mL, 84.0 mmol) was added followed by addition of a solution of NaOH (3.40 grams, 85.0 mmol) in H₂0 (50 mL) at 0°C. After 30 min the cooling bath was removed and the solution was concentrated to ca . 50 mL under reduced pressure. The aqueous phase was extracted with ethyl acetate (2 x 50 mL) . The aqueous layer was acidified at 0°C with cone, aqueous HCl (pH ~ 1) while the protected amino acid precipitated. The resulting solid was collected by filtration and washed with H₂0 (20 mL) . Overnight drying in an oven at ca. 50°C gave 27a as a colorless solid (14.6 grams, 71%) . The crude product was used without further purification. IR (KBr) : n_max3495, 3338, 3260, 1723, 1648, 1578, 1449, 1325, 1261, 1202, 1166, 1086 cm^"1; ^XH NMR (500 MHz, methanol-d⁴) : d 7.88-7.86 (m, 2 H, Ph) , 7.60-7.57 (m, 1 H, Ph) , 7.54-7.51 (m, 2 H, Ph) , 4.23 (t, 1 H, J = 6.0 Hz, CHC0₂H) , 2.66 (dd, 1 H, J^" = 6.0, 15.5 Hz, CHH(C=0)NH₂) , 2.60 (dd, .7 =6.0, 15.5 Hz, CHH(C=0) NH₂) ; ¹³C NMR (125 MHz, methanol-d⁴): d 174.3, 173.6, 142.1, 133.7, 130.0, 128.2, 53.9, 39.6; FAB-HRMS (M+H⁺) calcd 273.0545, found 273.0540.

Synthesis of compound 27b as shown in Figure 5. Compound 27b was prepared by the same procedure as for 27a using 2- naphthalenesulfonlyl chloride in lieu of phenylsulfonylchloride. Crude yield: 16.06 g (66%). IR (KBr): n_max3424, 3289, 2925, 1851, 1713, 1673, 1502, 1399, 1333, 1258, 1223, 1191, 1159, 1127, 1075, 1023, 964, 866, 822, 794, 714, 669, 638, 548, 477 cm^"1; E NMR (500 MHz, DMSO-d⁵) : d 8.40 (d, J = 1.0 Hz, 1 H, naphthyl), 8.15 (d, J^" = 9.0 Hz, 1 H, NHS0₂) , 8.12 (d, J^" = 8.0 Hz, 1 H, naphthyl), 8.07 (d, J = 9.0 Hz, 1 H, naphthyl), 8.01 (d, J = 8.0 Hz, 1 H, naphthyl), 7.81 (dd, J^" = 1.5, 8.8 Hz, 1 H, naphthyl), 7.68 (ddd, J = 1.5, 6.8, 7.5 Hz, 1 H, naphthyl), 7.64 (ddd, J = 1 . 5 , 6.8, 7.5 Hz, 1 H, naphthyl), 7.33 (bs, 1 H, CONHH) , 6.87 (bs, 1 H, CONHH) , 4.16 (bm, 1 H, CHCH₂) , 2.47 (dd, J = 7.0, 15.5 Hz, 1 H, CHCHH) 2.28 (dd, J = 6.5, 15.5 Hz, 1 H, CHCHH); ¹³C NMR (125 MHz, DMSO-d⁶) : d 172.0, 170.5, 138.4, 134.1, 131.6, 129.2, 129.0, 128.6, 127.8, 127.4, 127.1, 122.6, 52.5, 38.0; FAB-HRMS (M+H⁺) calcd 323.0702, found 323.0708.

Synthesis of compound 55(b) wherein -NH₂ substituent of compound 55 is replaced with -OH .

Step A: To a solution of 3-hydroxypropionic acid (.073 g, 0.16 mmol, 1.0 equiv.) was added DMF (0.5 mL, .32 M), imidazole (26.0 mg, 0.38 mmol, 2.4 equiv.) and TBDPSC1 (.046 mL, 0.19 mmol, 1.2 equiv.) and allowed to stir for 2.5 hour at 25 °C. The solution was then diluted with ether (10 mL) and then washed with a saturated solution of 5% hydrogen chloride (2X 10 mL) , water (2X 10 mL) , brine (IX 5 mL) and then dried over MgS04. The compound was purified by flash column chromatography (silica, 80% ether in light petroleum ether) and carried onto the next step as follows:

Step B: To a solution of phenylenediamine (1.08 g, 0.01 mol) in 5.5 N HCl (10 mL) was added the protected intermediate formed in step A (1.125g, 0.015 mol) at room temperature. The reaction mixture was refluxed for 24 h and then allowed to cool to room temperature. The solvent was removed in vacuo to give a precipitate, which was filtered and washed with ether; and then

Step C: The TBDPS group was removed as follows: A solution of intermediate from Step B (7.481 mmol) in THF (0.1M) was cooled to 0 °C and treated with azeotropically dried (benzene, 3 x 50 L) TBAF (22.44 mmol). The reaction mixture was stirred at 0 °C for 10 h and quenched with saturated aqueous NH₄C1. the two layers were separated and the aqueous phase was extracted with a mixture of ethyl acetate and ethyl ether. The combined organic phase was washed with brine, dried, and concentrated. Purification by silica gel column chromatography gave the pure compound 55(b) wherein -NH₂ substituent of compound 55 is replaced with -OH.

Synthesis of compound 55(c) wherein -NH₂ substituent of compound 55 is replaced with -SH .

To a solution of phenylenediamine (1.08 g, 0.01 mol) in 5.5 N HCl (10 mL) was added 3-mercaptopropionic acid (1.125g, 0.015 mol) at room temperature. The reaction mixture was refluxed for 24 h and then allowed to cool to room temperature. The solvent was removed in vacuo to give a precipitate, which was filtered and washed with ether to give the pure compound 55(c) wherein -NH₂ substituent of compound 55 is replaced with -SH.

Synthesis of compound 67 (b) and (c) wherein the -NH- group is substituted by either an -S- or -O- diradical (-NH- case is illustrated in Figure 9). To a solution of 57 (0.10 g, 0.20 mmol; synthesized above) in DMF (8 mL) was added 55 (b) or (c) (0.038 g, 0.22 mmol; synthesized above) and triethylamine (0.06 mL, 0.44 mmol) at room temperature. After stirring at 25 °C for 16 h, the reaction mixture was diluted with EtOAc (10 mL) and water (10 mL) . The layers were seperated and the aqueous layer was extracted with ethyl acetate (2 x 10 mL) . The organic extracts were collected and washed with water (2 x 10 mL) and brine (20 mL) and dried over Na₂S0₄. After filtration and evaporation under reduced pressure the residue was purified by flash chromatography (silica, ethyl acetate) to give 67 (b) or (c) .

Synthesis of compound 20 (b) or (c) wherein the -NH group is substituted by either an -S- or -0- diradical (-NH- case is illustrated in Figure 9) . To a solution of 67 (b) or (c)

(0.068 g, 0.11 mmol; synthesized above) in CH₂C1₂ (2 mL) was added trifluoroacetic acid (2 mL) at room temperature. After 4 h, the solvent was removed in vacuo to give an oil which after RP-HPLC (C-18) gave 20 (b) or (c) as a yellow solid.

Synthesis of compound 28a as illustrated in Figure 5. To a round-bottom flask equipped with a magnetic stirring bar was added an aqueous solution of NaOH (11.15 grams, 280.0 mmol) in water (50 mL) and cooled to 0°C. Bromine (2.60 mL, 50.0 mmol) was added dropwise within 5 min and the reaction mixture was stirred for further 5 min at this temperature. A solution of the protected amino acid 27a (10.44 grams, 38.0 mmol) in a solution of NaOH (3.10 grams, 70.0 mmol, 30 mL H₂0) was added in one portion at 0°C. Stirring was continued at this temperature for 20 min and upon removal of the cooling bath the reaction mixture was heated to 90°C for an additional 30 min. After cooling to 0°C the pH of the reaction mixture was a'djusted to 7 with concentrated and 1 M aqueous HCl. The resulting colourless precipitate was collected by filtration. The residue was washed with water, dried overnight in an oven at ca. 50°C to give 28a as colorless solid (6.95 grams, 75%). The crude product was used without further purification. IR (KBr): n_max3509, 3299, 3058, 2936, 1636, 1596, 1522, 1446, 1413, 1355, 1340, 1300, 1246, 1163, 1094, 1028, 924 cm^"1; ^λH NMR (500 MHz, DMSO-d⁶) : d 7.84-7.82 (m, 2 H, Ph) , 7.66-7.63 (m, 1 H, Ph) , 7.60-7.56 (m, 2 H, Ph) , 7.58 (bm, 1 H, NHS0₂Ph), 3.35 (bs, 2 H, NH₂) , 3.17 (dd, J^" = 4.5, 9.5 Hz, 1 H, CHCH₂) , 3.01 (dd, J = 2.5, 12.0 Hz, 1 H, CHH) , 2.80 (dd, J = 9.5, 12.0 Hz, 1 H, CHH); ¹³C NMR (125 MHz, DMSO-d⁵): d 169.4, 139.1, 132.7, 129.2, 126.8, 52.7, 41.7; FAB-HRMS (M+Na⁺) calcd 245.0596, found 245.0599.

Synthesis of compound 28b as illustrated in Figure 5. Compound 28b was prepared by the same procedure as for 28a using 27b instead of 27a. Crude yield: (11.88 grams, 81 %) as a beige- coloured solid. IR (KBr): n_max3338, 3241, 3056, 2831, 2601, 1651, 1604, 1513, 1463, 1404, 1382, 1335, 1151, 1076, 1039, 985, 955, 931, 913, 855, 814, 787, 749, 657, 618, 550, 480 cπf¹; ^XE NMR (500 MHz, DMSO-d⁶): d 8.48 (br. s, 1 H, naphthyl), 8.16-8.10 (2 bd, 2 H, naphthyl), 8.04 (d, J = 8.5 Hz, 1 H, naphthyl), 7.85 (dd, j = 2.0, 8.5 Hz, 1 H, naphthyl), 7.70 (ddd, J = 1.5, 7.0, 8.0 Hz, 1 H, naphthyl), 7.66 (ddd, J = 1.0, 7.0, 8.0 Hz, 1 H, naphthyl), 7.45 (bm, 1 H, NHS0₂), 3.54- 3.19 (bm, 2 H, NH₂) , 3.23 (dd, superimposed, J = 4.5, 9.5 Hz, 1 H, CHCH₂) , 3.04 (dd, J = 4.5, 12.00 Hz, 1 H, CHCHH), 2.83 (dd, J = 9.5, 12.00 Hz, 1 H, CHCHH); ¹³C NMR (125 MHz, DMSO- d⁶) : d 169.3, 136.1, 134.3, 131.6, 129.4, 129.2, 128.9, 128.0, 127.8, 127.6, 122.5, 52.7, 41.6; FAB-HRMS (M+H⁺) calcd 295.0753, found 295.0761.

Synthesis of compound 29a as illustrated in Figure 5. A sealed tube equipped with a magnetic stirring bar was charged with 28a (4.88 grams, 20.0 mmol) and 75 mL of anhydrous dimethoxyethane . After addition of 3.0 mL of cone. H₂S0₄ the reaction mixture was cooled to -78°C under an atmosphere of argon and 40.0 mL of isobutylene was condensed into the sealed tube. After sealing the cooling bath was removed and the reaction mixture was stirred for 48 hours at room temperature. The reaction mixture was poured into 100 mL of ice water. The aqueous solution was extracted with diethyl ether (40 mL) and then the pH of the aqueous phase adjusted to 12-13 with 6 N aqueous NaOH. The free amine was extracted with ethyl acetate (4 x 50 mL) and the combined organic extracts were washed succesively with saturated aqueous NaHC0₃-solution (50 mL) , 5 % aqueous KHS0₄-solution (50 mL) and brine (50 mL) . The organic phase was dried over MgS0₄, filtrated and the solvent removed in vacuo to give 29a (10.9 grams, 55.5%) as an off- white solid. The crude product was used without further purification. R_f = 0.27 (silica gel, ethyl acetate); IR (KBr) n_max3372, 3295, 2981, 2932, 1726, 1452, 1337, 1261, 1161, 1094, 945, 898, 845, 753 cm^"1; ^λH NMR (500 MHz, CDC1₃) : d 7.86- 7.84 (m, 2 H, Ph) , 7.58-7.54 (m, 1 H, Ph) , 7.51-7.48 (m, 1 H, Ph) , 3.76 (dd, J = 4.0, 5.5 Hz, 1 H, CHCH₂) , 3.02 (dd, J = 9.0, 13.0 Hz, 1 H, CHH), 2.88 (dd, J = 5.5, 13.0 Hz, 1 H, CHH), 1.27 (s, 9 H, 'Bu) ; ¹³C NMR (125 MHz, CDC1 : d 169.3, 139.7, 132.8, 129.1, 127.2, 82.8, 58.8, 44.9, 27.7; FAB-HRMS (M+H⁺) calcd 301.1222, found 301.1211.

Synthesis of 29b as illustrated in Figure 5. Compound 29b was prepared by the same procedure as for 29a using 28b instead of 28a. Crude yield: 4.56 g (51%) as an off-white solid. R_f = 0.25 (silica gel, ethyl acetate + 2 % v/v Et₃N); IR (KBr): n_max 3360, 3264, 3057, 2981, 2935, 2873, 2747, 1731, 1588, 1501, 1455, 1339, 1254, 1220, 1157, 1076, 952, 926, 823, 782, 747, 663, 619, 552, 481 cm^"1; Η NMR (500 MHz, CDC1₃) : d 8.40 (bs, 1 H, naphthyl), 7.92 (bd, J = 8.5 Hz, 2H, naphthyl), 7.86 (d, J = 8.0 Hz, 1H, naphthyl), 7.82 (dd, J = 1.5, 8.5 Hz, 1 H, naphthyl), 7.64-7.55 (2 x ddd, superimposed, J = 1.0, 7.0, 8.5 Hz, 2 H, naphthyl), 3.84 (dd, J = 4.2, 5.8 Hz, 1 H, CHCH₂) , 3.30-2.60 (bm, superimposed, 2 H, NH₂) , 3.03 (dd, J = 4.2,

13.4 Hz, 1 H, CHCHH), 2.88 (dd, J = 5.8, 13.4 Hz, 1 H, CHCHH), 1.08 (s, 9 H, t-Bu) ; ¹³C NMR (125 MHz, CDC1₃): d 169.2, 136.3, 134.9, 132.0, 129.5, 129.2, 128.9, 128.6, 127.8, 127.5, 122.4, 82.9, 58.6, 44.6, 27.5; FAB-HRMS (M+H⁺) calcd 351.1379, found 351.1371.

Synthesis of compound 31 as illustrated in Figure 6. To a suspension of the acid 30 (5.0 grams, 27 mmol; Aldrich) in toluene was added trimethylorthoacetate (17 mL, 135 mmol) . The mixture was heated to 80 °C for 12 hours and the solvent removed under reduced pressure to give 31 as a colorless solid (5.26 grams, 98%). R_f = 0.46 (silica gel, 25% ethyl acetate in hexane) ; IR (KBr): n_raax3061, 2960, 1714, 1614, 1542, 1438, 1351, 1297, 1262, 1233, 1130, 871, 755 cm^"1; Η NMR (500 MHz, CDC1₃) : d 8.74 (dd, J = (Η-Η) = 2.0 Hz, ⁴J (^-"F) = 7.0 Hz, 1 H, 2-Ar-H) , 8.32 (ddd, rΗ-Η) = 2.0 Hz, ⁴J (^XH-¹⁹F) = 4.5 Hz, U-'H) = 9.0, 1 H, 6-Ar-H) , 7.39 (dd, ³J (Η-Η) = 9.0 Hz, ³J (^-"F) = 10.5 Hz, 1 H, 5-Ar-H) ; ¹³C NMR (125 MHz, CDC1₃) : d 164.1, 159.1, 156.9, 136.5, 127.8, 118.8, 118.7, 52.9; FAB-HRMS (M+H⁺) calcd 200.0281 , found 200.0286.

Synthesis of compound 32 as illustrated in Figure 6. To a solution of 31 (4.0 grams, 20 mmol) in DMF (10 mL) were added ca . 4 g of 4 A molecular sieves and 4.46 g (0.22 mmol) of N₃(CH₂)₂OTBS at room temperature. After 10 min 2 mL (2.0 mmol) of a 1 M solution of TBAF in THF was added. The mixture was stirred for 4 hours at room temperatutre and then filtered through a short path of celite^®. The filtrate was taken up in ethyl acetate (100 mL) and successively washed with water, saturated aqueous NaHC0₃-solution and brine. The organic extract was dried over MgS0₄, filtered and the solvent removed under reduced pressure to give a yellow oil. Flash column chromatography (silica gel, 40% ethyl acetate in hexanes) gave 32 as a yellow solid (3.85 grams, 73%) . R_t = 0.35 (silica gel, 40% ethyl acetate in hexanes); IR (KBr): n_max2950, 2938, 2114, 1713, 1620, 1536, 1438, 1349, 1303, 1276, 1247, 1161, 1136, 918, 760 cm^"1; Η NMR (500 MHz, CDC1₃) : d 8.54 (d, J = 2.0 Hz, 1 H, Ar) , 8.22 (dd, J = 2 .0 , 9.0 Hz, 1 H, Ar) , 7.13 (d, J = 9.0 Hz, 1 H, Ar) , 4.32 (t, J^" = 5.0 Hz, 2 H, 0CH₂) , 3.94 (s, 3 H, 0CH₃), 3.71 (t, J = 5.0 Hz, 2 H, CH₂N₃) ; ¹³C NMR (125 MHz, CDC1₃) : d 164.7, 154.7, 135.3, 127.3, 123.3, 114.0, 68.8, 52.5, 49.7; FAB-HRMS (M+Na⁺) calcd 289.0549 , found 289.0553.

Synthesis of compound 33 as illustrated in Figure 6. To a solution of 32 (3.85 grams, 14.0 mmol) in 1, 4-dioxane :water (90 mL:30 mL) was added LiOH«H,0 (1.2 grams, 28 mmol). The reaction mixture was stirred at room temperature for 4 hours and then 40 mL of a saturated aqueous NH₄Cl-solution was added. The organic solvent was removed under reduced pressure to give a yellow slush. The slush was taken up in water and acidified with aqueous 1M KHS0₄-solution. The aqueous layer was then extracted with CH₂C1₂ (3 x 70 ml) . The combined organic extracts were dried over MgS0₄, filtered and the solvent removed under reduced pressure to give 33 as a yellow solid (3.50 grams, 99%). R_t = 0.10 (silica gel, 60 % ethyl acetate in hexanes) ; IR (KBr): n_max3087, 2964, 2877, 2659, 2539, 2120, 1699, 1616, 1534, 1429, 1359, 1282, 1163, 1138, 1079, 1039, 1002, 929, 847, 763, 687, 642, 546 cm^"1; ^XH NMR (500 MHz, methanol-d⁴): d 8.40 (d, J = 2.0 Hz, 1 H, Ar) , 8.22 (dd, J = 2.0, 9.0 Hz, 1 H, Ar) , 7.37 (d, J = 9.0 Hz, 1 H, Ar) , 4.37 (t, J = 4.5 Hz, 2 H, OCH₂) , 3.67 (t, J^" = 5.0 Hz, 2 H, CH₂N₃) ; ¹³C NMR (125 MHz, methanol-d⁴): d 167.4, 156.0, 140.9, 136.4, 127.9, 124.9, 115.7, 70.3, 51.1; FAB-HRMS (M+Na⁺) calcd 275.0392, found 275.0395.

Synthesis of compound 34 as illustrated in Figure 6. To a solution of amine 26 (0.33 grams, 1.10 mmol) and acid 33 (0.286 grams, 1.10 mmol) in CH₂C1₂ (30 mL) was added a catalytic amount of DMAP (0.03 grams, 0.22 mol) and DCC (0.26 grams, 1.1 mol) at room temperature. The reaction mixture was stirred for 4 hours at this temperature and the precipated dicyclohexyl urea was then filtered and the filtrate washed successively with water, saturated aqueous NaHCO ₃-solution and brine. The organic solvent was removed under reduced pressure to give an oil which after purification by flash column chromatography (silica gel, 60% ethyl acetate in hexanes) gave amide 34 as a yellow solid (2.48 grams, 82%) . R_f = 0.28 (silica gel, 60% ethyl acetate in hexanes); IR (KBr): n_max3343, 2977, 2933, 2112, 1738, 1710, 1619, 1531, 1498, 1366, 1333,

1280, 1161, 1084, 1047 cm^"1; Η NMR (500 MHz, CDC1₃) : d 8.23 (d, J^" = 2.0 Hz, 1 H, Ar) , 7.98 (dd, J = 2.0, 11.0 Hz, 1 H, Ar) , 7.40 (bt, 1 H, NHCO) , 7.39-7.31 (m, 5 H, Ph) , 7.09 (d, J = 11.0 Hz, 1 H, Ar) , 5.67 (d, J = 8.0 Hz, 1 H, NHC0₂) , 5.21 (s, 2 H, CH₂Ph) , 4.60-4.50 (bm, 1 H, CHCH₂) , 4.30 (t, J = 6.0 Hz, 2 H, OCH₂) , 3.95-3.85 (bm, 1 H, CHCHH), 3.78-3.70 (bm, superimposed, 1 H, CHCHH), 3.70 (t, J = 6.0 Hz, 2 H, CH₂N₃) , 1.43 (s, 9 H, ^fcBu) ; ¹³C NMR (125 MHz, CDC1₃) : d 170.0, 164.9, 153.8, 139.8, 135.0, 133.0, 128.7, 128.6, 126.9, 124.6, 114.3, 81.0, 68.8, 67.9, 49.8, 33.8, 28.2, 25.5, 24.8; FAB-HRMS (M+Cs⁺) calcd 661.1023, found 661.1050.

Synthesis of compounds 35ab as illustrated in Figure 6.

To a solution of the azide 34 (50 mg, 0.095 mmol) in a mixture of THF:H₂0 (8 mL THF: 0.04 mL H₂0) was added triphenylphosphine (50 mg, 0.19 mmol) . The reaction mixture was stirred at room temperature for 14 hours and the solvent was removed under reduced pressure. Purification of the crude residue by flash column chromatography (silica gel, 20 % methanol in dichloromethane) gave two major fractions (total yield 80 %) . Fraction 1: 17 mg (yellowish oil, 40 %), fraction 2: 17 mg (yellowish oil, 40 %) . Fraction 1 was positive in ninhydrin test while fraction 2 was negative. Fraction 1 35a R_s = 0.48 (silica gel, 20 % methanol in dichloromethane); ¹H NMR (500 MHz, CDC1₃) : d 8.22 (m, 1 H, Ar) , 7.94 (d, J = 9.0 Hz, 1 H, Ar) , 7.43-7.30 (m, 6 H) , 7.07 (d, J = 9.0 Hz, 1 H, Ar) , 5.80 (d, J = 6.0 Hz, 1 H, NHBoc), 5.19 (s, 2 H, CH₂Ph) , 4.54 (bm, 1 H, CHNHBoc), 4.21 (bm, 2 H, CH₂0Ar) , 3.87-3.76 ( , 2 H) , 3.19 (s, 2 H, CH₂NH₂) , 2.75 (bs, 2 H, NH₂), 1.41 (s, 9 H, Bu) ; FAB- HRMS (M+H⁺) calcd 503.2142, found 503.2162. Fraction 2 35b: R_t = 0.86 (silica gel, 20 % methanol in dichloromethane); ¹H NMR (500 MHz, CDC1₃) : d = 8.46 (m, 1 H, Ar) , 8.42 (t, J^" =6.5 Hz, 1 H, NHAr) , 7.79 (dd, J^" = 2.5 , 11.0 Hz, 1 H, Ar), 7.38- 7.28 (m, 5 H, Ar) , 7.21 (m, 1 H, NHCO) , 6.80 (d, J = 11.0 Hz, 1 H, Ar) , 5.85 (d, J = 9.0 Hz, 1 H, NHBoc), 5.19 (s, 2 H, CH₂Ph) , 4.53 (m, 1 H, CHNHBoc), 3.92 ( t , J = 6.5 Hz , 2 H, CH₂OH) , 3.88-3.73 (m, 2 H, CH₂NH(CO)), 3.52-3.38 (m, 2 H,

CH₂NHAr) , 1.41(s, 9 H, ^fcBu) ; FAB-HRMS (M+Cs⁺) calcd 635.118, found 635.110.

Synthesis of compound 10 as illustrated in Figure 6. To a solution of 35a (0.023g, 0.046 mmol) in a mixture of THF:H₂0 (6 mL:2 mL) was added LiOH»H,0 (4 mg, 0.092 mmol) at room temperature. The mixture was stirred for 4 hours and then acidified with acetic acid. The solvent was removed under reduced pressure and the residue used in the next step without further purification. To a solution of the crude acid in 2 ml of anhydrous DMF was added N, N-diisopropylethylamine (9 mL, 0.05 mmol) and lH-pyrazole carboxamidine *HC1 (8 mg, 0.05mmol). After 16 hours, the solvent was removed under reduced pressure and the residue was purified by RP-HPLC (C-18) to give 10 (3.25 mg, 13%) as a yellowish solid. J?_t = 20.5 min; Η ΝMR (500 MHz, D₂0) : d 8.33 (d, 1 H, J = 2.0 Hz, Ar) , 7.98 (dd, 1 H, J = 2.0, 9.0 Hz, Ar) , 7.30 (d, J = 9.0 Hz, 1 H, Ar) , 4.42 (m, 1 H, CHNHBoc) , 4.34 (t, J = 4.0 Hz, 2 H, CH₂NH(CO)), 3.82 (m, 2 H, NH₂(C=NH)NHCH₂, 3.63 (t, 2 H, J = 4.0 Hz, 2 H, CH₂0) ; FAB-HRMS (M+Cs⁺⁾ calcd 587.0866, found 587.0895.

Synthesis of compound 37 as illustrated in Figure 6. To a solution of 34 (0.10 grams, 0.019 mmol) in CH₂C1₂ (4 mL) at room temperature was added trifluoroacetic acid (4 mL) . The mixture was stirred for 2 hours. The solvent was removed in vacuo to give a yellowish oil, which after flash chromatography (silica, 5% methanol in dichloromethane) gave 37 as an oil (0.07 grams, 84%). J?_f = 0.19 (silica, 5% methanol in dichloromethane); Η NMR (500 MHz, CDC1₃) : d 8.21 (d, J = 2.0 Hz, 1 H, 2-Ar-H) , 7.95 (dd, J^" =2.0, 11.0 Hz, 1 H, 6-Ar-H) , 7.39-7.29 (m, 5 H, Ar) , 7.21 (bm, 1 H) , 7.05 (d, J = 9.0 Hz, 1 H) , 5.16 (s, 2 H, CH₂Ph) , 4.27 (t, J^" = 5.0 Hz, 2 H, CH₂OAr) , 3.67 (t, J = 5.0 Hz, 2 H, CH₂N₃) , 3.95-3.78 (bm, 1 H, CHNH₂) , 3.65-3.52 (bm, 1 H, CHCHH), 4.32-4.31 (bm, 1 H, CHCHH); ¹³C (125 MHz, CDC1₃): d 164.9, 153.7, 139.2, 135.1, 133.1, 128.6, 128.5, 128.4, 127.0, 124.6, 114.2, 68.7, 67.4, 49.7, 33.8, 25.5; FAB-HRMS (M+Cs⁺) calcd 561.0499, found 561.0507.

Synthesis of compound 38a as illustrated in Figure 6. To a solution of 37 (0.13 grams, 0.30 mmol) in CH₂C1₂ (10 mL) was added N, N-diisopropylethylamine (0.07 mL, 0.39 mmol) and benzenesulfonyl chloride (0.034 mL, 0.33 mmol) at room temperature. After 4 hours, the reaction mixture was diluted with CH₂C1₂ (10 mL) and water (10 mL) . The layers were seperated and the organic layer washed with a saturated solution of sodium bicarbonate and brine and dried (MgS0₄) . The solvent was removed in vacuo to give an oil, which after preparative thin layer chromatography (silica, 60% ether in hexanes) gave 38a as an oil (0.13 grams, 78%). R_f = 0.43 (silica, 60% ether in hexane) ; 'H ΝMR (500 MHz,CDCl₃): d 8.26 (d, J= 2.0 Hz, 1 H, 2-Ar-H) , 7.98 (dd, J = 2 . 0 , 9.0 Hz, 1 H, 6-Ar-H), 7.81 (d, J = 8.0 Hz, 2 H, Ar) , 7.53 (t, J = 8.0 Hz, 1 H, p-phenyl), 7.42 (t, J = 8.0 Hz, 2 H, m-phenyl ) , 7.31-7.30 (m, 3 H, Ar) , 7.22-7.21 (m, 2 H, Ar) , 7.08 (d, J^" = 9.0 Hz, 1 H, 5-Ar-H) , 7.03 (t, J =5.5 Hz, 1 H) , 5.03 (d, J = 12.0 Hz, 1 H, PhCHH) , 4.99 (d, J = 12.0 Hz, 1 H, PhCHH) , 4.29 (t, J = 4.5 Hz, 2 H, CH₂0) , 4.16 (dd, J = 4.0, 7.5 Hz, 1 H, CHCHH) , 3.92- 3.87 (m, 1 H, CHCH₂) , 3.72-3.67 (m, superimposed, 3 H , CHCHH, CH₂N₃) ; "C NMR (125 MHz, CDC1₃) : d 169.2, 165.2, 153.7, 139.3, 138.7, 134.3, 133.1, 132.9, 129.1, 128.4, 128.3, 126.9, 126.5, 124.9, 114.1, 68.7, 68.1, 55.4, 49.7, 42.4 ; FAB-HRMS (M+Cs⁺) calcd 701.0431, found 701.0442.

Synthesis of compound 38b as shown in Figure 6. Compound 38b was prepared by the same procedure as for 38a using 1- Naphthalene sulfonyl chloride in lieu of phenyl sulfonyl chloride. Yield: (0.031g, 57%) as an oil. R_f = 0.18 (5% methanol in dichloromethane); IR (thin film): n_max3277, 2930, 2112, 1740, 1652, 1618, 1523, 1496, 1348, 1280, 1162, 1125, 984, 910, 772 cm^"1. ^XH NMR (500 MHz, CDC1₃) : d 8.60 (d, J = 11.0 Hz, 1 H, naphthyl), 8.21 (dd, J = 2.0, 9.3 Hz, 1 H, naphthyl), 8.03 (d, J^" = 2.9 Hz, 1 H, 2-Ar-H), 8.01 (d, J = 10.4 Hz, 1 H, naphthyl), 7.87 (d, J = 9.3 Hz, 1 H, naphthyl), 7.81 (dd, J = 2.9, 11.0 Hz, 1 H, 6-Ar-H), 7.62 (ddd, J = 1.7, 8.7, 8.7 Hz, 1 H, naphthyl), 7.54 (ddd, J = 1.3, 8.8, 8.8 Hz, 1 H, naphthyl), 7.47 (dd, J = 9.4, 10.1 Hz, 1 H, naphthyl), 7.28-7.22 (m, 3 H, Ph) , 7.12-7.07 (m, 2 H, Ph) , 6.98 (d, J = 11.0 Hz, 1 H, 5-Ar- H) , 6.69 (dd, J = 7.5 Hz, 1 H, NHCO) , 6.22 (d, J = 9.5 Hz, 1 H, NHS0₂) , 4.89 (d, J = 15.0 Hz, 1 H, CHHPh) , 4.83 (d, J = 15 Hz, 1H, CHHPh), 4.25 (t, J = 6.0 Hz, 2 H, OCH₂) , 4.13 (ddd, J = 5.4, 9.4, 9.5 Hz, 1 H, CHCH , 3.74 (ddd, J = 5.4, 7.4, 17.5 Hz, 1 H, CHCHH), 3.69 (t, J = 6.1 Hz, 2 H, CH₂N₃) , 3.67 (ddd, superimposed, J = 7.5, 9.0, 17.5 Hz, 1 H, CHCHH); ¹³C NMR (125 MHz, CDC1₃) : d 169.3, 165.1, 153.7, 139.1, 134.8, 134.4, 134.0, 133.5, 132.9, 129.9, 129.0, 128.6, 128.5, 128.3, 127.7, 126.3, 124.8, 124.1, 114.0, 68.7, 67.9, 55.7, 49.8, 42.2; FAB- HRMS (M+Cs^+> calcd 751.0587, found 751.0599.

Synthesis of compounds 39a and 41a as illustrated in Figure 6. Compounds 39a and 41a were prepared by the same procedure as for 35ab using compound 38b in lieu of 38a. Yield: (FI = 0.029 grams, F2 = 0.028 g) , total yield (80%). F2 was positive in ninhydrin test while Fl was not. R_f (Fl) 41a = 0.39 (silica, 10% methanol in dichloromethane); Η NMR (500 MHz, CDC1₃) : d 8.35 (bs, 1 H, 2-Ar-H), 8.31 (bs, 1 H,

CH₂NHAr) , 7.76-7.60 (m, superimposed, 3 H, Ar) , 7.50 (bs, 1 H) , 7.38 (t, J = 9.0 Hz, 1 H, Ar) , 7.28 (t, J = 9.0 Hz, 2 H, Ar) , 7.26-7.13 (m, 5 H, Ar) , 6.86 (d, J = 11.0 Hz, 1 H, Ar) , 6.64 (d, J = 11.0 Hz, 1 H, NHS0₂) , 4.92 (d, J = 15.0 Hz, 1 H, PhCHH), 4.86 (d, J = 15.0 Hz, 1 H, PhCHH), 4.26-4.23 (m, 1 H, CHCH₂) , 3.80-3.67 (m, superimposed, 4 H, HOCH₂, CHCH₂) , 3.34- 3.31 (bm, CH₂NHAr) , 2.92 (bs, CH₂OH) ; R_f (F2) 39a = 0.16 (silica, 20 % methanol in dichloromethane); Η NMR (500 MHz, CDC1₃) : d 8.24 (bs, 1 H, Ar) , 7.94 (d, J = 9.0 Hz, 1 H, Ar) , 7.80 (d, J = 8.0 Hz, 2 H) , 7.49 (t, J = 8.0 Hz, 1 H, Ph) , 7.40 (t, J = 8.0 Hz, 2 H, Ph) , 7.30-7.28 (m, 3 H, Ar) , 7.19-7.18 (m, superimposed, 3 H, Ar, NH(CO) ) , 7.02 (d, J = 9.0 Hz, 1 H, Ar) , 5.01 (d, J^" = 12.5 Hz, 1 H, PhCHH) , 4.97 (d, J = 12.5 Hz, 1 H, PhCHH), 4.18-4.15 (m, superimposed, 3 H, CHCH₂, OCH₂) , 3.86-3.84 (m, 1 H, CHCHH), 3.70-3.68 (m, 1 H, CHCHH), 3.15- 3.13 (bm, 2 H, OCH₂NH₂) , 2.82 (bm, 2 H, NH₂) ; ¹³C NMR (125 MHz, CDC1₃) : d 169.5, 165.4, 154.4, 139.9, 138.8, 134.4, 133.0, 132.8, 129.0, 138.5, 128.4, 127.0, 126.3, 125.0, 114.1, 71.4, 68.0, 55.4, 42.3, 40.7; FAB-HRMS (M+Cs⁺) calcd 675.0526, found 675.0546.

Synthesis of compound 11 as illustrated in Figure 6.

Compound 11 was prepared by the same procedure as for 10 using 40a in lieu of 36b. Yield: (3.31 mg, 13%). ^XH NMR (500 MHz, methanol-d⁴): d 8.26 (d, J = 2.0 Hz, 1 H, Ar) , 8.04 (dd, J^" = 2.0, 8.5 Hz, 1 H, Ar) , 7.82-7.80 (m, 2 H, Ph) , 7.47-7.36 (m, 4 H, 5-ArH, Ph) , 4.35 (t, J = 5.0 Hz, 2 H, OCH₂) , 4.19 (dd, J = 4.0, 14.0 Hz, 1 H, CHCH₂), 3.75 (dd, J = 4.0, 14.0 Hz, 1 H, CHCHH), 3.68 (t, J = 5.0 Hz, 2 H, CH₂NH(C=N)), 3.47 (dd, J = 11.0, 14.0 Hz, 1 H, CHCHH).

Synthesis of compound 12 as illustrated in Figure 6. To a solution of the benzyl ester 41a (0.10 grams, 0.22 mmol) in THF:H₂0 (3 mL : 1 mL) was added LiOH»H₂0 (18.5 mg, 0.44 mmol) at room temperature. After stirring for 4 hours, the reaction mixture was acidified with acetic acid and the solvent removed in vacuo to give the crude acid 42a. To a solution of the acid 42a in DMF (5 mL) was added N, N- diisopropylethylamine (38 L, 0.22 mmol). After stirring at 50°C for 16 hours, the solvent was removed in vacuo to give an oil, which after RP- HPLC (C-18) gave 12 (5.4 mg, 5%) as a yellowish solid. R_t = 14.9 min; Η ΝMR (600 MHz, CDC1₃) : d 8.26 (d, J^" =2.0 Hz, 1 H, Ar) , 7.67-7.65 (m, 2 H, Ph) , 7.64 (dd, J = 2.0, 9.0 Hz, Ar) , 7.24-7.18 (m, 3 H, Ph) , 7.06 (d, J^" = 9.0 Hz, Ar) , 4.49 (t, J = 4.0 Hz, 2 H, CH₂OH) , 4.15 (dd, J = 6.0 , 10.0 Hz, 1 H, CHCH₂) , 3.86 (t, J^" = 4.0 Hz, 2 H, CH₂Ν (C=ΝH) ΝH₂) , 3.70 (dd, J = 6.0, 14.0 Hz, 1 H, CHCHH), 3.35 (dd, J =10.0, 14.0 Hz, 1 H, CHCHH); ¹³C NMR (150 MHz, CDC1₃): d 167.6, 164.9, 147.2, 141.7, 132.4,

130.5, 129.6, 127.7, 126.8, 125.6, 125.5, 122.2, 112.5, 70.4,

4.2.6, 28.7, 23.2. Electrospray mass spectrum (M+H⁺) calcd 495, found 495.

Synthesis of compounds 39b as illustrated in Figure 6. To a solution of the azide 38b (0.031 grams, 0.05 mmol) in THF:H₂0 (8 mL:0.04 mL) was added triphenylphosphine (0.026 grams, 0.1 mmol) . After stirring at room temperature for 12 hours, the solvent was removed in vacuo to give a white solid. The solid was purifed by preparative thin layer chromatography (silica, 20% methanol in dichloromethane) to give 39b as an oil (0.013 grams, 44%). J?_£ = 0.1 (silica gel, 10% methanol in dichloromethane); IR (thin film): n._^3361, 3282, 3070, 2922, 2851, 1742, 1650, 1620, 1527, 1456, 1349, 1322, 1280, 1162, 1126, 989, 910 cm^"1; *H NMR (500 MHz, CDC1₃) : d = 8.63 (d, J = 10.8 Hz, 1 H, naphthyl), 8.17 (dd, J = 1.0, 9.1 Hz, 1 H, naphthyl), 8.02 (d, J = 2.5 Hz, 1 H, Ar) , 7.92 (d, .7 = 10.3 Hz, 1 H, naphthyl), 7.77 (d, J = 10.3 Hz, 1 H, naphthyl), 7.72 (dd, J = 2.6, 11.0 Hz, 1 H, Ar) , 7.58 (dd, J = 8.3, 8.3 Hz, 1 H, naphthyl), 7.49 (dd, J = 7.3, 7.3 Hz, 1 H, naphthyl), 7.41 (dd, J = 7.5, 7.5 Hz, 1 H, naphthyl), 7.23-7.16 (m, 3 H, Ph) , 7.09-7.04 (m, 2 H, Ph) , 6.84 (d, J = 11.1 Hz, 1 H, Ar) , 4.83 (d, J = 15.2 Hz, 1 H, CHHPh), 4.76 (d, J^" = 15.2 Hz, 1 H, CHHPh), 4.23 (dd, J = 5.8, 9.1 Hz, 1 H, CHCH₂) , 4.10-4.04 (bm, 2 H, OCH₂) , 3.95-3.61 (bm, 5 H, CH₂NH₂, CHCHH), 3.18-3.05 (bm, 1 H, CHCHH) ; ¹³C NMR (125 MHz, CDCl₃): d 169.6, 165.3, 154.2, 146.9, 134.6, 134.5, 134.0, 133.9, 133.2, 129.8, 129.0, 128.6, 128.5, 128.4, 128.2, 127.8, 127.0, 125.9, 124.9, 124.2, 124.1, 114.3, 67.6, 55.9, 42.0, 40.5, 29.6; FAB-HRMS (M+Cs ⁺ calcd 725.0682, found 725.0695.

Synthesis of compound 13 as illustrated in Figure 6.

Compound 13 was prepared by the same procedure as for 10 using compound 40b in lieu of 36b. Yield: (1.8 mg, 15%) as a yellowish solid. R_t = 21.2 min; Η NMR (500 MHz, methanol-d⁴): d 8.63 (d, J = 9.0 Hz, 1 H, naphthyl), 8.17 (dd, J = 1.5, 7.5 Hz, 1 H, naphthyl), 7.94 (d, J = 8.5 Hz, 1 H, naphthyl), 7.88 (d, J^" = 2.5 Hz, 1 H, Ar) ,7.76-7.70 (m, superimposed, 2 H, 6- Ar-H, naphthyl-), 7.57 (ddd, J = 1.0, 6.5, 9.3 Hz, 1 H, naphthyl), 7.47 (dd, J = 7.5, 8.0 Hz, 1 H, naphthyl), 7.42 (ddd, J^" = 1.0, 7.0, 7.5 Hz, 1 H, naphthyl), 7.25 (d, J = 9.0 Hz, 1 H, Ar) , 4.36 (t, J = 5.0 Hz, 1 H, CH₂0) , 4.18 (dd, J = 4.5, 9.5 Hz, 1 H, CHCHH), 3.72 (t, J = 5.0 Hz, 2 H, CH₂NH) , 3.65 (dd, J = 4.5, 13.5 Hz, 1 H, CHCHH), 3.41 (dd, J = 9.5, 13.5 Hz, 1 H, CHCHH) ; Electrospray mass spectrum calcd (M+H⁺) 545, found 545.

Synthesis of compound 51 as illustrated in Figure 7. To a solution of aminoethanol (43) (1.0 mL, 16.0 mmol) in DMF (30 mL) was added 1, 3-Bis- ( ert-Butoxycarbonyl) -2-methyl-2- thiopseudourea (48) (4.81 grams, 16.0 mmol), triethylamine (4.63 mL, 32.0 mmol) and mercury (II) dichloride (4.48 grams, 16.0 mmol) at room temperature. After 4 hours, the reaction mixture was diluted with ethyl acetate and filtered over a short path of celite^®. The filtrate was succesively washed with water (2 x 20 mL) , brine (20 mL) and dried over MgSO ₄. After filtration and evaporation of the solvent under reduced pressure the crude compound was purified by flash column chromatography to give 51 as a colourless solid (4.95 grams, 98%). R_f = 0.43 (silica gel, 50 % ethyl acetate in hexanes); IR (KBr): n_max3329, 3142, 2977, 2934, 2870, 1724, 1644, 1443, 1412, 1360, 1299, 1103, 1052, 1027, 864, 809, 778 cm^"1; ^XH NMR (500 MHz, CDC1₃) : d 11.48 (bs, 1 H, NHC0₂) , 8.66 (m, 1 H,

CH₂NH) , 4.54 (bs, 1 H, OH), 3.74 (t, J = 4.5 Hz, 2 H, CH₂OH) , 3.54 (dt, J = 5.5, 5.5 Hz, 2 H, CH₂NH) , 1.47 (s, 9 H, ^fcBu) , 1.45 (s, 9 H, ^cBu) ; ¹³C NMR (125 MHz, CDCl₃): d 162.8, 157.4, 153.1, 83.5, 79.2, 63.1, 44.4, 28.2, 28.0; FAB-HRMS (M+H⁺) calcd 304.1872, found 304.1878.

Synthesis of compound 52 as illustrated in figure 7. To a solution of piperazine (44) (3.45 mL, 12.0 mmol) in DMF (10 mL) was added 1 , 3-Bis- ( ert-Butoxycarbonyl) -2-methyl-2- thiopseudourea (48) (0.87 grams, 3.00 mmol) at room temperature. After 14 hours, the reaction mixture was diluted with ethyl acetate and water. The layers were seperated and the organic layer was washed succesively with water (2 x 20 mL) , brine (20 mL) and dried over Na₂S0₄. The solvent was removed under reduced pressure to give 52 as a colorless solid (0.93 grams, 95%). R_t = 0.34 (silica gel, 10% methanol in dichloromethane); IR (KBr): n_max 3294, 2980, 2931, 2856, 1749, 1664, 1605, 1527, 1448, 1367, 1305, 1230, 1149, 1116, 1019, 893, 842, 730, 682 cm^"1. Η NMR (500 MHz, methanol-d⁴): d 3.48 (t, J = 5.0 Hz, 4 H, (CH₂)₂N(C=N) , 2.83 (t, J = 5.0 Hz, 4 H,

(CH₂)₂NH), 1.46 (s, 9 H, ^fcBu) ; ¹³C NMR (125 MHz, methanol-d⁴): d 154.4, 81.4, 48.2, 46.0, 28.6; FAB-HRMS (M+Na⁺⁾ calcd 341.1226, found 341.1235.

Synthesis of compound 53 as illustrated in Figure 7. To a solution of aminoethanethiol (45) (114 mg, 1.00 mmol) in DMF (5 mL) was added N, N' -Bis- ert-Butoxycarbonylthiourea (49) (276 mg, 1.00 mmol) and triethylamine (2.79 mL, 2.00 mmol) at room temperature. After 14 hours, the reaction mixture was diluted with 5 mL of H₂0 and extracted with ethyl acetate (3 x 10 mL) . The combined organic extracts were washed with brine and dried over MgS0₄. After filtration and evaporation of the solvent under reduced pressure the crude compound was purified by flash column chromatography (silica gel, 25 % diethyl ether in hexanes) to give 53 as an airsensitive colorless solid (191 mg, 59.8%) . R_t = 0.16 (silica, 25 % diethyl ether in hexanes); IR (KBr): n_max3327, 3132, 2978, 2931, 1726, 1643, 1565, 1431, 1363, 1329, 1280, 1227, 1133, 1088, 1058, 855, 809, 760, 606 cm^"1; Η NMR (500 MHz, CDC1₃) : d 11.45 (bs, 1 H, (C=N)NH (C=0) ) , 8.61 (bt, J^" = 5.9 Hz, 1 H, CH₂NH) , 3.74 (bdt, J = 6.0, 6.5 Hz, 2 H, CH₂NH) , 2.85 (t, J = 6.5 Hz, 2 H, CH₂SH) , 1.47 (s, 9 H, ^fcBu) ; ¹³C NMR (125 MHz, CDC1₃): d 163.4, 156.1, 153.1, 83.2, 79.3, 39.2, 37.0, 28.3, 28.1 ; FAB-HRMS calcd only S-S-dimer observed!

Synthesis of compound 54 as illustrated in Figure 7. To a solution of ethylenediamine (54) (3.45 mL, 51.6 mmol) in DMF (50 mL) was added 1, 3-Bis- ( ert-Butoxycarbonyl) -2-methyl-2- thiopseudourea (48) (3.00 grams, 10.33 mmol), triethylamine ("2.88 mL, 20.7 mmol) and mercury ( II) chloride (2.81 grams, 10.3 mmol) at room temperature. After 4 hours, the reaction mixture was diluted with 20 mL of ethyl acetate and filtered over a short path of celite^®. The filtrate was succesively washed with H₂0 (2 x 50 L) , brine (50 mL) and dried over MgS0₄. Flash column chromatography (silica gel, 20 % MeOH in ethyl acetate + 2 % v/v Et₃N) gave 54 as a colourless solid (1.60 grams, 51.2%). R = 0.30 (silica gel, 20 % MeOH in ethyl acetate + 2 % v/v Et₃N) ; IR (KBr): n_max3446, 3389, 3259, 2978, 2819, 1728, 1706, 1656, 1626, 1521, 1485, 1365, 1253, 1171, 1093, 1049, 888, 802, 738, 699, 562 cm^"1; *H NMR (500 MHz, CDC1₃) : d 11.38 (bs, 1 H, (C=N)NH (C=0) ) , 8.61 (bt, 1 H, CH₂NH(C=N) ) , 3.45 (bdt, J = 5.5, 5.5 Hz, 2 H, CH₂NH) , 2.85 (t, J = 5.5 Hz, 2 H, CH₂NH₂) , 1.46 (s, 9 H, ^fcBu) ; ¹³C NMR (125 MHz, CDC1₃) : d 163.4, 156.4, 153.1, 83.1, 79.2, 41.8, 40.9, 28.2; FAB-HRMS (M+H⁺) calcd 303.2032, found 303.2037.

Synthesis of compound 55 as illustrated in Figure 7. To a solution of phenylenediamine (1.08 grams, 0.01 mol) in 5.5 N HCl (10 mL) was added b-alanine (47) (1.125g, 0.015 mol) at room temperature. The reaction mixture was refluxed for 24 hours and then allowed to cool to room temperature. The solvent was removed in vacuo to give a precipitate, which was filtered and washed with ether (1.70 grams, 73%) . R_f = 0.12 (20% methanol in dichloromethane); ^XH NMR (500 MHz, D₂0) : d 7.73-7.72 (m, 2 H, Ar) , 7.55-7.53 (m, 2 H, Ar) , 3.61-3.55 (m, 4 H, CH₂CH₂); ¹³C NMR (125 MHZ, D₂0) : d FAB-HRMS (M+H⁺) calcd 162.1031, found 162.1029.

Synthesis of compound 56 as illustrated in Figure 7. To a solution of ethylenediamine (46) (1.0 L, 0.015 mol) in DMF (10 mL) was added 2- (3 , 5-Dimethylpyrazolyl) -4 , 5- dehydroimidazole hydrobromide (50) (3.67 grams, 0.015 mol) and N, N-diisopropylethylamine (2.61 mL, 0.015 mol) at room temperature. After stirring for 11 hours, ether (12 mL) was added to the reaction mixture and a white precipitate formed. The precipitate was filtered and washed with ether to give 56 (1.59 grams, 51%). IR (KBr): n_max 3164, 1681, 1599, 1484, 1287, 1211, 1137, 1069, 952 cm^"1; ^XH ΝMR (500 MHz, D₂0) : d 3.54 (bs, 4 H, ΝHCH₂CH₂ΝH) , 3.17 (t, J^" = 6.0 Hz, CH₂NH) , 2.65 (t, J = 6.0 Hz, CH₂NH₂) ; ¹³C NMR (125 MHz, D₂0) : d 160.9, 45.3, 43.6, 40.3; FAB-HRMS (M+H⁺) calcd 129.1140, found 129.1134.

Synthesis of compound 58 as illustrated in Figure 8. To a solution of 3-nitro-4-fluoro benzoic acid (30) (1.59 grams,

8.57 mmol; Aldrich) in benzene (40 mL) was added DMF (0.03 mL, 0.40 mmol) and oxalylchloride (3.73 mL, 20.2 mmol) at 0°C. After 6 hours, the solvent was removed in vacuo . The resulting yellow viscous oil (1.73 grams, 8.57 mmol) was dissolved in CH₂C1₂ (20 mL) . The solution was cooled to 0°C and triethylamine (1.28 mL, 9.20 mmol) was added. A solution of the protected 2-amino alanine tert-butylester 29a (2.32 grams, 7.70 mmol) in CH₂C1₂ (40 mL) was added. After 4 hours, the reaction mixture was diluted with water and the aqueous phase was extracted with dichloromethane (2 x 50 mL) after phase seperation. The combined organic extracts were washed with saturated aqueous NaHC0₃-solution and dried over MgS0₄. After filtration and evaporation of the solvent under reduced pressure the crude compound was purified by flash column chromatography (silica gel, 45 % ethyl acetate in hexanes) to give 58 as a yellow foam (3.90 grams, 98%). R_t = 0.19 (silica gel, 40 % ethyl acetate in hexanes); IR (KBr): n_^ 3286, 2980, 2936, 1730, 1653, 1619, 1537, 1493, 1448, 1349, 1314, 1159, 1131, 1092 cm^"1; H NMR (500 MHz, CDC1₃) : d 8.56 (dd, ⁴J ^H^H) = 2.5 Hz, ⁴J (^-"F) = 7.5 HZ, 1 H, 2-Ar-H), 8.12 (ddd, ⁴J (^XH- ^XH) = 2.5 Hz, ⁴J ^H-^F) = 4.0 Hz, ³J (¹H-¹H) = 9.0 Hz, 1 H, 6- Ar-H) , 7.84 (d, J = 7.5 Hz, 2 H, o-phenyl), 7.58 (d, J =7.5 Hz, 1 H, p-phenyl), 7.50 (t, J =7.5 Hz, 2 H, m-Ar ) , 7.34 (dd, ³J ^H^H) = 9.0 Hz, ³J (^-"F) = 10.0 Hz, Ar-H), 7.13 (t, J = 5.5 Hz, 1 H, (C=0)NH), 5.89 (d, J = 8.0 Hz, 1 H, CHNHS0₂Ph) , 3.97-3.92 ( , 2 H, CHH, CHCH₂) , 3.60-3.54 (m, 1 H, CHH), 1.29 (s, 9 H, ^fcBu) ; ¹³C NMR (125 MHz, CDC1₃): d 168.1, 164.5, 158.1, 156.0, 138.6, 134.2, 134.1, 133.2, 130.9, 129.2, 127.2, 125.6, 118.9, 118.7, 84.2, 55.8, 42.5, 27.6; FAB-HRMS (M+Cs⁺) calcd 600.0217, found 600.0195.

Synthesis of compound 59 as illustrated in Figure 8.

Compound 59 was prepared by the same procedure as for compound 58 using 2-Naphthalene sulfonyl chloride in lieu of phenyl sulfonyl chloride. Yield: (985 mg, 96%) as an off-white solid. R_t = 0.24 (silica gel, 50 % ethyl acetate in hexanes); IR (KBr): n_nax3395, 3297, 3083, 2981, 2937, 1734, 1671, 1620, 1534, 1494, 1460, 1345, 1264, 1156, 1128, 1079, 977, 918, 833, 750, 661, 617, 549, 479 cm^"1; Η NMR (500 MHz, CDC1₃) : d 8.46 (dd, ^H-Η) = 2.5 Hz, J(¹H-¹⁹F) = 7.0 Hz , 1 H, 2-Ar-H), 8.38 (d, J = 2.0 Hz, 1 H, naphthyl), 8.02 (ddd, \7(Η-Η) = 2.5 Hz, ^<J{ ^XH-¹⁹F ) = 4.0 Hz, ^{3 "}(¹H-¹H) = 8.8 Hz, 1 H, 6-Ar-H), 7.90 (bd, superimposed, J = 8.5 Hz, 1 H, naphthyl), 7.88 (bd, superimposed, J = 8.5 Hz, 1 H, naphthyl), 7.83 (bd, J = 8.0 Hz, 1 H, naphthyl), 7.79 (dd, J = 2.0, 8.0 Hz, 1 H, naphthyl), 7.62 (ddd, J = 1.0, 7.5, 8.5 Hz, 1 H, naphthyl), 7.58 (ddd, J = 1.0, 7.5, 8.5 Hz, 1 H, naphthyl), 7.27 (br. dd, J^" = 6.0, 8.5 Hz, 1 H, CONH) , 7.18 (bdd, ³J(¹H-¹H) = 9.0 Hz, 'J^H-^F) = 10.0 Hz, 1 H, 5-Ar-H) , 6.15 (d, J^" = 8.0 Hz, 1 H, NHS0₂) , 4.06 (ddd, J = 4.0, 5.5, 8.0 Hz, 1 H, CHCH₂) , 3.93 (ddd, J = 4.0, 6.0, 11.0 Hz, 1 H, CHCHH), 3.57 (ddd, J = 5.5 Hz, 8.5 Hz, 1 H, CHCHH), 1.17 (s, 9 H, 'Bu) ; ¹³C NMR (125 MHz, CDC1₃): d 168.3, 164.3, 158.0, 155.8, 135.5, 134.7, 134.1, 134.0, 131.8, 130.5, 129.5, 129.1, 128.6, 127.7, 125.4, 122.0, 118.6, 118.4, 83.9, 55.9, 42.3, 27.4; FAB-HRMS (M+Cs⁺) calcd 650.0373, found 650.0358.

Synthesis of compound 60 as illustrated in Figure 8. To a round bottom flask equipped with a magnetic stirring bar was placed NaH (60% suspension in mineral oil) (0.16 grams, 3.96 mmol) and THF (10 mL) at 0°C. To the stirred suspension was added a solution of 51 (0.55 grams, 1.80 mmol) in THF (5 mL) . Stirring was continued at this temperature for an additional 30 min and the resulting grey suspension was ready for use. A round bottom flask equipped with a magnetic stirring bar was charged with the aromatic fluoride 58 (0.1 grams, 0.30 mmol) and DMF (10 mL) . The solution was cooled to 0°C and 5.5 mL of the previously prepared suspension was added by means of a syringe. After 8 hours at 0°C the reaction was stopped by addition of water (10 mL) and diluted with ethyl acetate. The aqueous phase was seperated and extracted with ethyl acetate (3 x 25 mL) . The combined organic extracts were washed successively with H₂0 (2 x 10 L) and brine (10 mL) and dried over MgS0₄. After filtration and evaporation under reduced pressure the residue was purified by flash column chromatography (silica, 60% ethyl acetate in hexanes) to give 60 as a yellowish foam (0.15 grams, 66%) . JR_£ = 0.18 (silica gel, 50% ethyl acetate in hexanes); IR (KBr): n_max 3331, 2978, 2951, 1733, 1645, 1619, 1532, 1367, 1319, 1277, 1144, 1051, 1025 cm^"1; Η NMR (500 MHz, CDC1₃) : d 11.43 (bs, 1 H, (C=N)NH(C=0) ) , 8.76 (bt, J = 5.5 Hz, 1 H, CH₂NH(C=N) ) , 8.32 (d, J = 2.5 Hz, 1 H, Ar) , 8.00 (dd, J = 2.5, 9.0 Hz, 1 H, Ar) , 7.85-7.84 (m, 2 H, Ph) , 7.58 (t, J = 8.0 Hz , 1 H, Ph) , 7.49 (t, J = 8.0 Hz, 2 H, Ph) , 7.20 (d, J = 9.0 Hz, 1 H, Ar) , 6.95 (t, J = 8.0 Hz, 1 H, NHCO) , 5.84 (d, J = 7.5 Hz, 1 H, HNS0₂) , 4.28 (t, J = 5.5 Hz, 2 H, CH₂0) , 3.96-3.87 (m, superimposed, 4 H, CHCH₂, CH₂NH(C=N)), 3.60-3.54 (m, 1 H, CHCH₂), 1.50 (s, 9 H, ^cBu) , 1.48 (s, 9 H, ^cBu) , 1.28 (s, 9 H, ^cBu) ; ¹³C NMR (125 MHz, CDC1₃) : d 168.2, 165.0, 163.3, 156.5, 154.5, 154.1, 150.9, 139.4, 138.8, 133.1, 132.7, 129.2, 127.2, 126.5, 125.0, 114.5, 84.0, 83.4, 68.1, 55.9, 42.4, 39.4, 28.3, 28.0, 27.6; FAB-HRMS (M+Cs⁺) calcd 883.1949, found 883.1970.

Synthesis of compound 11 as illustrated in Figure 8. To a solution of 60 (30.0 mg, 0.04 mmol) in CH₂C1₂ (2 mL) trifluoroacetic acid (2 mL) was added dropwise. The reaction mixture was stirred at 25°C for 2 hours. The solvents were removed under reduced pressure and the residue was purified by RP-HPLC (C-18) to give 11 as yellowish solid (22.0 mg, 92%). J?_t = 12.2 min; IR (KBr): n_max3418, 1679, 1529, 1433, 1354, 1319, 1278, 1198, 1161, 1092, 1046, 932, 837, 802, 756, 688 cm -1 ^XH NMR (500 MHz, methanol-d⁴): d 8.26 (d, J = 2.0 Hz, 1

H, Ar) , 8.04 (dd, J = 2.0, 8.5 Hz, 1 H, Ar) , 7.82-7.80 (m, 2 H, Ph) , 7.47-7.36 (m, 4 H, Ar) , 4.35 (t, J = 5.0 Hz, 2 H, OCH₂), 4.19 (dd, J = 4.0, 14.0 Hz, 1 H, CHCH₂) , 3.75 (dd, J = 4.0, 14.0 Hz, 1 H, CHCHH), 3.68 (t, J^" = 5.0 Hz, 2 H,

CH₂NH(C=N)), 3.47 (dd, J^" = 11.0, 14.0 Hz, 1 H, CHCHH); ¹³C NMR (125 MHz, methanol-d⁴): d 167.7, 155.0, 142.2, 140.7, 134.5, 133.6, 130.0, 128.2, 125.9, 115.7, 69.8, 43.3, 41.8, 25.2; FAB-HRMS (M+H⁺) calcd 495.1298, found 495.1311.

Synthesis of compound 61 as illustrated in Figure 8 : To a solution of 58 (100 mg, 0.20 mmol) in DMF (10 mL) was added 53 (68 mg, 0.22 mmol) . After stirring at room temperature for 4 hours, the reaction mixture was diluted with water (10 mL) and the aqueous phase extracted with ethyl acetate (3 x 10 mL) . The combined organic extracts were washed succesively with water (2 x 10 L) and brine (20 mL) and dried over Na₂S0₄. After filtration and evaporation under reduced pressure the residue was purified by flash column chromatography (silica gel, 50 % ethyl acetate in hexanes) to give 61 as a yellowish foam (110 mg, 73%) . R_f = 0.48 (silica gel, 60% ethyl acetate in hexanes); IR (film): n_max3318, 2925, 1723, 1623, 1517, 1412, 1324, 1158 cm^"1; ^XH NMR (500 MHz, CDC1₃) : d 11.47 (bs, 1 H, (C=N) H (C=0) ) , 8.59 (d, J = 2.5 Hz , 1 H, Ar) , 8.56 (t, J = 10.0 Hz, 1 H, NH) , 8.43 (t, J = 10.0 Hz, 1 H, NH) , 7.93 (dd, J = 2.5 Hz, 10.0 Hz, 1 H, Ar) , 7.84 (d, J = 9.0 Hz, 2 H, Ph) , 7.53 (t, J = 10.0 Hz, 1 H, Ph) , 7.46 (t, J = 10.0 Hz, 2 H, Ph) , 7.21 (d, J = 10.0 Hz, 1 H, Ar) , 6.81 (t, J = 10.0 Hz, 1 H, CONH) , 5.87 (d, J = 10.0 Hz, 1 H, NHS0₂) , 3.98-3.93 (m, 1 H, CHCH₂) , 3.87-3.82 (m, 1 H, CHCHH) , 3.72-3.55 (m, 5 H, CHCHH, NHCH₂, CH₂NH(C=N) ) , 1.52 (s, 9 H, ^fcBu) , 1.47 (s, 9 H, ^fcBu) , 1.27 (s, 9 H, ^fcBu) ; ¹³C NMR (125 MHz, CDC1₃) : d 168.4, 165.7, 163.3, 156.6, 153.2, 146.9, 139.1,

134.7, 133.0, 131.4, 129.1, 127.2, 126.2, 121.0, 114.4, 83.7, 83.5, 79.5, 56.2, 42.4, 42.2, 39.0, 28.3, 28.0, 27.6; FAB-HRMS (.M+Cs⁺) calcd 882.2109, found 882.2129.

Synthesis of compound 14 as illustrated in Figure 8. Compound 14 was prepared by the same procedure as 11 using 61 in lieu of 60. Yield: (33.2 mg,92%) as a yellow solid. R_t = 15.9 min; IR (KBr): n_max3364, 3245, 2998, 2584, 1669, 1624, 1555, 1520, 1433, 1313, 1198, 1161, 923, 756, 722 cm^"1; ^XH NMR (500 MHz, methanol-d⁴): d 8.61 (d, J = 2.5 Hz, 1 H, Ar) , 7.92 (dd, J = 2.5, 9.0 Hz, 1 H, Ar) , 7.81 (d, J = 7.0 Hz, 2 H, Ph) , 7.47-7.40 (m, 3 H, Ph) , 7.11 ( d, J = 9.0 Hz, 1 H, Ar) , 4.19 (dd, J^" = 5.0, 9.0 Hz, 1 H, CHCH₂), 3.72 (dd, J = 5.0, 13.5 Hz, 1 H, CHCHH), 3.67 (t, J = 6.0 Hz, 2 H, NHCH₂), 3.52 (t, J = 6.0 Hz, 2 H, NHCH₂) , 3.46 (dd, J = 9.0, 13.5 Hz, 1 H, CHCHH); ¹³C NMR (125 MHz, methanol-d⁴): d 168.3, 159.0, 148.0, 142.1,

135.8, 133.6, 132.9, 130.0, 127.8, 125.0, 122.3, 114.8 43.2, 42.5, 41.1, 31.1; FAB-HRMS (M+H⁺) calcd 494.1458, found 494.1444.

Synthesis of compound 62 as illustrated in Figure 8. To a solution of 54 (1.60 mg, 5.0 mmol) in THF (50 mL) was added NaH (60 % suspension in mineral oil) (200 mg, 5.00 mmol) at 0°C. After 15 min the resulting thiolate solution was ready for use. To a solution of 58 (100 mg, 0.20 mmol) in DMF (10 mL) was added the thiolate solution (5.0 mL, 0.5 mmol) by syringe. After 12 hours at room temperature the reaction was stopped by addition of water (10 mL) and diluted with ethyl acetate. After phase seperation the aqueous phase was extracted with ethyl acetate (3 x 25 mL) . The combined organic extracts were washed succesively with water (2 x 10 mL) and brine (10 mL) and dried over MgS0₄. After filtration and evaporation under reduced pressure the residue was purified by flash column chromatography (silica gel, 40 % ethyl acetate in hexanes) to give 62 as a yellowish foam (35 mg, 23%) . R_f = 0.32 (silica gel, 40 % ethyl acetate in hexanes); ^XH NMR (500 MHz, CDC1₃) : d 11.45 (bs, 1 H, (C=N) NH (C=0) ) , 8.65 (bt, superimposed, J = 4.5 Hz, 1 H, CH₂NH(C=N) ) , 8.63 (d, superimposed, J^" = 2.0 Hz, 1 H, Ar) , 8.22 (d, J^" = 8.5 Hz, 1 H, Ar) , 8.15 (dd, J = 2.0, 8.5 Hz, 2 H, Ar) , 7.84 (d, J = 8.0 Hz, 2 H, Ph) , 7.56 (t, J = 7.5 Hz, 1 H, Ph) , 7.48 (bdd, J = 7.0,

8.0 Hz, 2 H, Ph) , 6.98 (t, J = 5.5 Hz, 1H, CONH) , 5.72 (d, J = 7.0 Hz, 1 H, NHS0₂) , 3.99-3.93 (bm, 1 H, CHCH₂) , 3.88 (ddd, J = 4.5, 5.5, 13.5 Hz, 1 H, CHCHH) , 3.70-3.58 (m, 3 H, CHCHH, CH₂NH(C=N) ) , 3.26 (t, J^" = 8.0 Hz, 2 H, SCH₂) , 1.57 (s, 9 H, ^fcBu) , 1.50 (s, 9 H, Bu) , 1.30 (s, 9 H, ^fcBu) ; ¹³C NMR (125 MHz, CDC1₃) : d 168.2, 165.1, 163.4, 156.3, 153.1, 145.3, 141.0, 138.9, 133.1, 132.3, 130.3, 129.2, 127.7, 127.2, 124.7, 84.0, 83.5, 79.6, 55.9, 42.4, 39.2, 30.1, 28.4, 28.0, 27.6; FAB-HRMS (M+Cs⁺) calcd 899.1720, found 899.1753.

Synthesis of compound 15 as illustrated in Figure 8. Compound 15 was prepared by the same procedure as for 11 using 62 in lieu of 60. Yield: (23.0 mg, 92%) as a yellow solid. R_t = 16.0 min; ^λU NMR (500 MHz, methanol-d⁴): d 8.58 (d, J = 2.0 Hz, 1 H, Ar) , 8.06 (dd, J = 2.0 , 8.5 Hz , 1 H, Ar) , 7.82 (d, J = 7.0 Hz, 2 H, Ph) , 7.71 (d, J = 8.5 Hz, 1 H, Ph) , 7.48-7.41 (m, 3 H, Ar) , 4.23 (dd, J = 5.0, 9.0 Hz, 1 H, CHCH₂) , 3.80- 3.76 (m, 1 H, CHCHH), 3.56 (t, J^" = 6.5 Hz, 2 H, CH₂NH(C=N)), 3.50-3.43 (m, 1 H, CHCHH), 3.34 (t, J = 6.5 Hz, 2 H, SCH₂) ; ¹³C NMR (125 MHz, methanol-d⁴): d 167.6, 155.2, 142.1, 140.7, 133.5, 133.3, 132.5, 128.3, 128.0, 126.0, 43.4, 40.7, 32.3; FAB-HRMS (M+H⁺) calcd 511.1070, found 511.1058. Synthesis of compound 65 as illustrated in Figure 8. To a solution of 58 (100 mg, 0.20 mmol) in DMF (10 L) was added 52 (68 mg, 0.22 mmol) . After 6 hours, the reaction mixture was diluted with water (25 mL) and ethyl acetate. After phase separation the aqueous phase was extracted with ethyl acetate (3 x 30 mL) . The combined organic extracts were washed succesively with water (2 x 20 mL) and brine (20 mL) and dried over Na₂S0₄. After filtration and evaporation under reduced pressure the residue was purified by flash column chromatography (silica gel, 40 50 % ethyl acetate in hexanes) to give 65 as a yellowish foam (120 mg, 83%) . R_{f =} 0.30 (silica gel, 40 % ethyl acetate in hexanes); IR (film): n^ 3266, 2977, 1743, 1621, 1520, 1451, 1367, 1304, 1158, 1130, 1094, 1014 cm^"1; ^XH NMR (500 MHz, CDC1₃): d 10.22 (bs, 1 H, (C=N)HN(C=0) ) , 8.29 (d, J = 2.5 Hz, 1 H, Ar) , 7.92 (dd, J = 2.5, 9.0 Hz, 1 H, Ar) , 7.85-7.84 (m, 2 H, Ph) , 7.83-7.82 (m, 1 H) , 7.56 (t, J = 7.0 Hz, 1 H, Ph) , 7.48 (t, J = 7.0 Hz, 2 H, Ar-H), 7.08 (d, J = 9.0 Hz, 1 H, Ar-H), 6.93 (t, J = 6.0 Hz, 1 H, CO(NH)), 5.85 (d, J = 8.0 Hz, 1 H, NHS02 ) , 3.96-3.87 ( , 2 H, CHCH₂, CHCHH), 3.80-3.70 (bm, 4 H, NH(CH₂)₂), 3.59-3.54 (m, 1 H, CHCHH), 3.23-3.21 (m, 4 H, N(CH₂)₂), 1.48 (s, 18 H, ^fcBu) , 1.26 (s, 9 H, 'Bu); ¹³C NMR (500 MHz, CDC1₃): d 168.3, 165.3, 155.2, 147.5 140.9, 138.8, 133.1, 132.0, 129.2, 127.2, 126.3, 126.0, 119.9, 84.0, 56.0, 50.3, 42.2, 28.1, 27.6; FAB-HRMS (M+Cs⁺) calcd 908.2265, found 908.2233.

Synthesis of compound 16 as illustrated in Figure 8. Compound 16 was prepared by the same procedure as for 11 using 66 in lieu of 65. Yield: (15.0 mg, 93%) as a yellowish solid. R_t = 15.3 min; IR (KBr): n_max3367, 3239, 2925, 2857, 1662, 1613,

1523, 1449, 1388, 1320, 1199, 1173, 1135, 1093, 992, 837, 802, 721 cm^"1; ^XH NMR (500 MHz, methanol-d⁴): d 8.22 (d, J = 2.0 Hz, 1 H, Ar) , 7.95 (dd, J = 2.0, 8.5 Hz, 1 H, Ar) , 7.79 (m, 2 H, Ph) , 7.47-7.38 (m, 3 H, Ph) , 7.32 (d, J = 8.5 Hz, 1 H, Ar) , 4.21 (dd, J = 5.0, 9.0 Hz, 1 H, CHCH₂) , 3.74 (dd, J = 5.0, 10.0 Hz, 1 H, CHCHH), 3.67-3.65 (m, 4 H, N(CH₂)₂), 3.49-3.44 (m, 1 H, CHCHH), 3.31-3.29 (m, 4 H, N(CH₂)₂); ¹³C NMR (125 MHz, methanol-d⁴) : d 172.6, 167.9, 158.4, 148.3, 142.8, 142.2, 129.9, 56.6, 50.9, 46.3, 43.3; FAB-HRMS (M+H⁺) calcd 520.1614, found 520.1630.

Synthesis of compound 63 as illustrated in Figure 8. To a solution of 51 (130 mg, 0.43 mmol) in THF (5.0 mL) was added NaH (60 % suspension in mineral oil) (70 mg, 1.74 mmol) at 0°C. Stirring was continued at this temperature for additional 15 min and the resulting grey suspension was ready for use. To a solution of 59 (200 mg, 0.39 mmol) in DMF (20 mL) was added the alkoxide (2.5 mL) . After stirring for 1 hour at 0°C the remaining 2.5 mL of the alkoxide was added. After 3 hours at 0°C the reaction was stopped by addition of 10 mL of a saturated aqueous NH₄Cl-solution and diluted with ethyl acetate. After phase seperation the aqueous phase was extracted with ethyl acetate (3 x 25 mL) . The combined organic extracts were washed succesively with H₂0 (2 x 10 mL) and brine (10 mL) and dried over MgS0₄. After filtration and evaporation under reduced pressure the residue was purified by flash column chromatography (silica gel, 50 % ethyl acetate in hexanes) to give 63 as a yellow solid (211 mg, 69%) . R_f = 0.16 (silica gel, 50 % ethyl acetate in hexanes) ; IR (KBr) : n_max 3330, 2979, 2934, 1728, 1620, 1570, 1531, 1416, 1329, 1281, 1156, 1079, 1023, 970, 916, 816, 753, 660, 618, 552, 477 cm^"1; ^XH NMR (500 MHz, CDC1₃): d 11.45 (bs, 1 H, (C=N) H (C=0) ) , 8.78 (bt, 1 H, CH₂NH(C=N) ) , 8.37 (s, 1 H, Ar) , 8.26 (d, J = 2.0 Hz, 1 H, naphthyl), 7.92-7.87 (2 x d, J^" = 8.0 Hz, 2 H, naphthyl), 7.90 (d, J = 8.5 Hz, 1 H, Ar) , 7.83 (d, J = 8.5 Hz, 1 H, naphthyl), 7.79 (dd, J = 2.0, 8.5 Hz, 1 H, naphthyl), 7.64- 7.55 (2 x br. dd, 2 H, naphthyl), 7.07 (d, J^" = 8.5 Hz, 1 H,

Ar) , 6.90 (dd, ^" = 5.5, 5.5 Hz, 1 H, CH₂NH(C=0) ) , 5.95 (d, J^" = 7.5 Hz, 1 H, NHS0₂) , 4.22 (t, J = 5.3 Hz, 2 H, OCH₂) , 4.02 (ddd, J = 4.0, 7.5, 8.5 Hz, 1 H, CHCH₂) , 3.93-3.83 (m, superimposed, 3 H, CHCHH, CH₂NH(C=N) ) , 3.55 (ddd, J = 5.5, -8.5, 13.5 Hz, 1 H, CHCHH) , 1.50 (s, 9 H, ^fcBu) , 1.47 (s, 9 H, ^fcBu) , 1.17 (s, 9 H, ^fcBu) ; ¹³C NMR (125 MHz, CDC1₃) : d 168.3, 164.9, 156.4, 154.0, 152.9, 139.3, 135.6, 134.9, 132.6, 132.0, 129.6, 129.2, 129.1, 128.7, 127.8, 127.7, 127.6, 126.3, 125.0, 122.1, 114.4, 84.0, 83.5, 68.0, 56.1, 42.3, 39.5, 28.3, 28.0, 27.5; FAB-HRMS (M+Cs⁺) calcd 933.2105, found 933.2116.

Synthesis of compound 17 as illustrated in Figure 8.

Compound 17 was prepared by the same procedure as for 11 using 63 in lieu of 60. Yield: (32.7 mg, 99%) as an off white to brownish solid. R_t = 14.5 min. IR (KBr): n_max = 3421, 2999, 2898, 1657, 1635, 1528, 1383, 1351, 1322, 1276, 1198, 1157, 1132, 1080, 1046, 979, 823, 754, 660, 550 cm^"1; ^XH NMR (500

MHz, methanol-d⁴): d 8.15 (s, 1 H, naphthyl), 7.93 (d, J = 2.0 Hz, 1 H, Ar) , 7.72 (d, J^" = 8.0 Hz, 1 H, naphthyl), 7.69-7.58 (m, 4 H, naphthyl, Ar) , 7.42-7.35 (2 x ddd, superimposed, 2 H, naphthyl), 6.92 (d, J = 9.0 Hz, 1 H, Ar) , 4.21 (dd, J^" = 4.5, 9.8 Hz, 1 H, CHCH₂), 4.13 (t, J = 5.0 Hz, 2 H, OCH₂) , 3.61

(dd, J = 4.5, 13.5 Hz, 1 H, CHCHH) , 3.57 (t, J = 4.5 Hz, 2 H, CH₂NH(C=N) ) , 3.28 (dd, J = 9.8 Hz, 13.5 Hz, 1 H, CHCHH); ¹³C NMR (125 MHz, methanol-d⁴): d 172.8, 167.1, 159.3, 154.9, 140.1, 139.5, 135.9, 134.1, 133.4, 130.3, 130.2, 129.5, 128.8, 128.7, 128.4, 127.3, 125.7, 123.5, 115.3, 69.7, 56.8, 43.1, 41.8; FAB-HRMS (M+H⁺) calcd 545.1455, found 545.1471.

Synthesis of compound 64 as illustrated in Figure 8. To a solution of 59 (50 mg, 0.10 mmol) in l-methyl-2-pyrrolidinone (1 mL) was added 53 (58 mg, 0.19 mmol) at room temperature.

After 4 hours, the reaction mixture was diluted with water (10 mL) and the aqueous phase extracted with ethyl acetate (3 x 10 mL) . The combined organic extracts were washed succesively with water (2 x 5 mL) and brine (5 mL) and dried over MgSO ₄. After filtration and evaporation under reduced pressure the residue was purified by flash column chromatography (silica gel, 50 % ethyl acetate in hexanes) to give 64 as a yellow solid (76 mg, 99%). R_f = 0.22 (silica gel, 50 % ethyl acetate in hexanes) ; IR (KBr): n_max3300, 3065, 2975, 2931, 1734, 1660, 1620, 1535, 1497, 1347, 1261, 1159, 1129, 1079, 972, 917, 817, 751, 661, 551, 477 cm^"1; ^XH NMR (500 MHz, CDC1₃) : d 11.49 (bs, 1 H, (C=N)NH(C=0) ) , 8.58 (bt, 1H, CH,NH(C=N) ) , 8.47 (d, J = 2.0 Hz, 1 H, Ar) , 8.41 (dd, J = 5.5 Hz, 1 H, NHCH₂) , 8.37 (d, J^" = 2.0 Hz, 1 H, naphthyl), 7.90-7.84 (m, superimposed, 3 H, naphthyl), 7.86 (dd, J = 2.0 , 9.0 Hz, 1 H, Ar) , 7.79 (dd, J^" = 2.0, 8.5 Hz, 1 H, naphthyl), 7.59 (ddd, J = 1.5 Hz, 7.0, 7.0 Hz, 1 H, naphthyl), 7.54 (ddd, J = 1.5 Hz, 7.0, 7.0 Hz, 1 H, naphthyl) , 7.12 (d, J = 9.0 Hz, 1 H, Ar) , 6.69 (t, J = 5.5 Hz, 1 H, CH₂NH(C=0) ) , 5.89 (d, J = 8.0 Hz, 1 H, NHS0₂) , 4.03 (ddd, J = 4.0, 8.0, 8.5 Hz, 1 H, CHCH₂) , 3.85 (ddd, J = 4.0, 6.0, 14.0 Hz, 1 H, CHCHH), 3.70 (bdt, J = 5.5, 5.5 Hz, 2 H, NHCH₂) , 3.61-3.50 (m, 3 H, CHCHH, CH₂NH(C=N)), 1.52 (s, 9 H, ^fcBu) , 1.47 (s, 9 H, ^fcBu) , 1.18 (s, 9 H, ^fcBu) ; ¹³C NMR (125 MHz, CDC1₃) : d 168.5, 165.6, 156.6, 153.2, 146.9, 136.0, 134.8, 134.6, 132.0, 131.3, 129.6, 129.2, 128.9, 128.6, 127.8, 127.6, 126.0, 122.2, 120.8, 114.3, 83.8, 83.6, 56.4, 42.4, 42.2, 39.1, 28.3, 28.0, 27.6; FAB-HRMS (M+Cs⁺) calcd 932.2265, found 932.2285.

Synthesis of compound 18 as illustrated in Figure 8.

Compound 18 was prepared by the same procedure as 11 using 64 in lieu of 60. Yield: (81.7 mg, 90%) as an orange yellow solid. R_t = 12.4 min; IR (KBr): n_max3364, 1676, 1624, 1556, 1520, 1426, 1315, 1241, 1200, 1158, 1133, 1076, 1025, 999, 824, 757, 719, 660, 549, 479 cm^"1; ^lE NMR (500 MHz, methanol- d⁴) : d 8.17 (bs, 1 H, naphthyl), 8.14 (d, J = 2.0 Hz, 1 H, Ar) , 7.72 (d, J = 8.0 Hz, 1 H, naphthyl), 7.68-7.65 ( , 2 H, naphthyl), 7.57 (bd, superimposed, J^" = 9.5 Hz, 1 H, naphthyl), 7.55 (dd, superimposed, J = 2.0, 9.0 Hz, 1 H, Ar) , 7.41 (ddd, J = 1.5, 7.0, 8.0 Hz, 1 H, naphthyl), 7.36 (ddd, J = 1.5, 7.0, 8.0 Hz, 1 H, naphthyl), 6.74 (d, J = 9.0 Hz, 1 H, Ar) , 4.25 (dd, J = 4.5, 10.0 Hz, 1 H, CHCH₂) , 3.62 (dd, J = 4.5, 14.0

Hz, 1 H, CHCHH), 3.52 (t, J = 6.0 Hz, 2 H, NHCH₂), 3.41 (t, J = 6.0 Hz, 2 H, NHCH₂) , 3.30 (dd, J = 10.0, 14.0 Hz, 1 H, CHCHH); ¹³C NMR (125 MHz, methanol-d⁴): d 173.0, 167.8, 147.8, 139.5, 135.9, 135.3, 133.4, 130.3, 130.2, 129.3, 128.7, 128.6, 128.3, 127.2, 123.5, 121.5, 114.5, 57.0, 42.9, 42.5, 41.5; FAB-HRMS (M+Na⁺) calcd 566.1434, found 566.1453. Synthesis of compound 66 as illustrated in Figure 8. To a solution of 59 (150 mg, 0.29 mmol) in DMF (5 mL) was added 52 (190 mg, 0.58 mmol) at room temperature. After 20 hours, the reaction mixture was diluted with water (25 mL) and ethyl acetate. After phase seperation, the aqueous phase extracted with ethyl acetate (3 x 30 mL) . The combined organic extracts were washed succesively with water (2 x 20 mL) and brine (20 mL) and dried over MgS0₄. After filtration and evaporation under reduced pressure the residue was purified by flash column chromatography (silica gel, 40 % ethyl acetate in hexanes) to give 66 as a yellow solid (240 mg, 99%). R_f = 0.33 (silica gel, 50 % ethyl acetate in hexanes); IR (KBr): n_max 3397, 2979, 2933, 1741, 1610, 1524, 1454, 1367, 1303, 1239, 1157, 1015, 975, 834, 752, 661, 615, 552, 477 cm^"1; ^λE NMR (500 MHz, CDC1₃) : d 11.49 (bs, 1H, (C=N)NH (C=0) , 8.38 (bs, 1 H, naphthyl), 8.24 (d, J= 2.0 Hz, 1 H, Ar) , 7.90 (bd, J = 7.5 Hz, 1 H, naphthyl), 7.87 (brd, J^" = 9.0 Hz, 1 H, naphthyl), 7.83 (dd, superimposed, J = 2.0, 8.5 Hz, 1 H, Ar) , 7.82 (d, superimposed, J = 8.0 Hz, 1 H, naphthyl), 7.79 (dd, J = 2.0, 8.5 Hz, 1 H, naphthyl), 7.64-7.55 (2 x bddd, superimposed, 2 H, naphthyl), 7.13 (bm, 1 H, NH(C=0)), 6.98 (d, J = 9.0 Hz, 1 H, Ar) , 4.01 (ddd, J = 3.5, 8.0, 9.0 Hz, 1 H, CHCH₂) , 3.88 (ddd, J^" = 4.0, 6.0, 13.5 Hz, 1 H, CHCHH), 3.73 (bm, 4 H, NCH₂) , 3.55 (ddd, J^" = 5.5, 8.5, 13.5 Hz, 1 H CHCHH), 3.18 (bm, 4 H, NCH₂) , 1.48 (s, 18 H, "Ε ) , 1.15 (s, 9 H, ^cBu) ; ¹³C NMR (125 MHz, CDC1₃) : d 168.6, 165.1, 155.2, 147.3, 140.9, 135.6, 134.9, 132.0, 129.6, 129.2, 129.0, 128.7, 127.8, 127.7, 126.2, 126.0, 122.1, 119.8, 119.7, 83.9, 56.1, 50.3, 42.2, 28.2, 28.0, 27.3; FAB-HRMS (M+Cs⁺) calcd 958.2422, found 958.2458.

Synthesis of compound 19 as illustrated in Figure 8. Compound 19 was prepared by the same procedure as for 11 using 66 in lieu of 60. Yield: (31.9 mg, 93%) as a yellowish solid. R_t = 11.1 min; IR (KBr): n_max3401, 3297, 3251, 2996, 2928, 1659, 1613, 1523, 1451, 1385, 1323, 1199, 1157, 1138, 1078, 992, 808, 753, 720, 660, 549 cm^"1; ^XH NMR (500 MHz, methanol- d⁴) : d 8.19 (bs, 1 H, naphthyl) , 7.93 (d, J = 2.0 Hz, 1 H, Ar) , 7.76 (bd, J = 9.0 Hz, 1 H, naphthyl), 7.71-7.61 (m, superimposed, 3 H, naphthyl, Ar) , 7.55 (dd, J = 2.0 Hz, 8.8 Hz, 1 H, naphthyl), 7.44-7.36 (2 x ddd, superimposed, 2 H, naphthyl) , 6.91 (d, J = 8.5 Hz, 1 H, Ar) , 4.21 (dd, J = 4.5, 9.5 Hz, 1 H, CHCH₂), 3.61 (dd, J = 4.5, 13.5 Hz, 1 H, CHCHH), 3.55 (m, 4 H, NCH₂) , 3.29 (dd, J = 9.5, 13.5 Hz, 1 H, CHCHH), 3.15-3.09 (m, 4 H, NCH₂) ; ¹³C NMR (125 MHz, methanol-d⁴): d 167.6, 158.5, 148.2, 142.1, 139.4, 136.0, 133.5, 133.3, 130.4, 130.3, 129.7, 128.9, 128.5, 127.3, 126.7, 123.6, 121.2, 50.9, 49.6, 48.6, 46.4; FAB-HRMS (M+Cs⁺) calcd 702.0747, found 702.0784.

Synthesis of compound 67 as illustrated in Figure 9. To a solution of 57 (0.10 grams, 0.20 mmol) in DMF (8 mL) was added 55 (0.038 grams, 0.22 mmol) and triethylamine (0.06 mL, 0.44 mmol) at room temperature. After stirring at 25°C for 16 hours, the reaction mixture was diluted with EtOAc (10 mL) and water (10 mL) . The layers were seperated and the aqueous layer was extracted with ethyl acetate (2 x 10 mL) . The organic extracts were collected and washed with water (2 x 10 mL) and brine (20 mL) and dried over Na₂S0₄. After filtration and evaporation under reduced pressure the residue was purified by flash chromatography (silica, ethyl acetate) to give 67 as a yellowish solid (110 mg, 92%) . R_f = 0.43 (silica, ethyl acetate); ^XH NMR (500 MHz, methanol-d⁴): d 8.57 (d, J = 2.0 Hz, 1 H, Ar), 7.96 (bm, 1 H, Ar) , 7.83 (dd, J = 2.0, 9.0 Hz, 1 H, Ar) , 7.80-7.78 (m, 2 H, Ar) , 7.48-7.39 (m, 4 H, Ar) , 7.18 (dd, J = 4.0 , 6.0 Hz, 2 H) , 7.06 (d, J = 9.0 Hz,

1 H, Ar) , 4.12 (dd, J = 6.0, 8.0 Hz, 1 H, CH₂CH) , 3.89 (t, J =7.0 Hz, 2 H, CH₂Ar) , 3.65 (dd, J = 6.0, 14.0 Hz, 1 H, CHHCH) ,

3.46 (dd, J = 8.0, 14.0 Hz, 1 H, CHHCH), 3.26 (t, J = 7.0 Hz,

2 H, CH₂NH) , 1.22 (s, 9 H, ^fcBu) ; ¹³C NMR (125 MHz, methanol- d⁴) : d 170.4, 168.1, 164.8, 153.6, 147.9, 142.2, 135.6, 133.6, 132.6, 132.4, 130.1, 128.1, 127.7, 123.5, 121.8, 114.9, 83.3, 57.3, 43.2, 42.3, 27.9; Electrospray mass spectrum (M+H⁺) calcd 609, observed 609. Synthesis of compound 20 as illustrated in Figure 9. To a solution of 57 (0.068 grams, 0.11 mmol) in CH₂C1₂ (2 mL) was added trifluoroacetic acid (2 mL) at room temperature. After 4 hours, the solvent was removed in vacuo to give an oil which after RP-HPLC (C-18) gave 20 as a yellow solid (0.056, 97%). ^λE NMR (500 MHz, methanol-d⁴): d 8.65 (d, J = 1.0 Hz, 1 H, Ar) , 7.93 (dd, J = 1.0, 9.0 Hz, 1 H, Ar) , 7.81 (d, J = 8.0 Hz, 2 H, Ph) , 7.74 (dd, J = 3.0, 6.0 Hz, 2 H, Ar) , 7.58 (dd, J = 3.0, 6.0 Hz, Ar) , 7.48 (t, J = 7.0 Hz, 1 H, Ph) , 7.43 (t, J = 8.0 Hz, 2 H, Ph) , 7.16 (d, J = 9.0 Hz, 1 H, Ar) , 4.20 (dd, J = 5.0, 9.0 Hz, 1 H, CHCHH), 4.04 (t, J^" = 6.5 Hz, 2 H, CH₂Ar) , 3.74 (dd, J = 5.0, 14.0 Hz, 1 H, CHCHH), 3.54 (t, J = 6.5 Hz, 2 H, CH₂NH) , 3.45 (dd, J = 9.0 , 14.0 Hz, 1 H, CHCHH); ¹³C NMR (125 MHz, methanol-d⁴): d 172.6, 168.1, 152.6, 147.3, 142.0, 135.7, 133.5, 133.1, 132.4, 132.3, 130.0, 127.9, 127.8, 127.4, 122.5, 114.8, 114.6, 56.8, 43.2, 41.2, 27.2; FAB-HRMS (M+Cs⁺) calcd 685.0482, found 685.0461.

Synthesis of compound 68 as illustrated in Figure 9. To a solution of 57 (0.06 grams, 0.13 mmol) in DMF (10 mL) was added 56 (0.03 grams, 0.14 mmol) and triethylamine (0.04 mL, 0.29 mmol) at room temperature. After 12 hours, the solvent was removed in vacuo to give 68 as a crude yellow oil (0.09 grams, 110%). R_f = 0.23 (40% methanol in dichloromethane); ¹H NMR (500 MHz, methanol-d⁴): d 8.63 (d, J^" = 2.0 Hz, 1 H, Ar) ,

7.93 (dd, J = 2.0, 9.0 Hz, 1 H, Ar) , 7.82 (d, J = 6.5 Hz, 2 H, Ph) , 7.48-7.42 (m, 3 H, Ph) , 7.09 (d, J = 9.0 Hz, 1 H, Ar) , 4.08-4.06 (m, 1 H, CHCHH), 3.68-3.62 (m, superimposed, 5 H, NHCH₂CH₂NH, CHCHH), 3.50-3.44 (m, 1 H, CHCHH), 3.30 (t, J^" = 3.5 Hz, 2 H, CH₂NHAr) , 1.24 (s, 9 H, ^£Bu) ; Electrospray mass spectrum calcd (M+H⁺) 573, found 573.

Synthesis of compound 21 as illustrated in Figure 9. To a solution of 68 (0.09 grams, 0.14 mmol) in CH₂C1₂ (5 mL) was added trifluoroacetic acid (5 mL) at room temperature. After 4 hours, the solvent was removed in vacuo to give an oil which after RP-HPLC (C-18) gave 21 as a yellow solid (0.07 grams, 83%) R_t = 14.0 min; ^λE NMR (500 MHz, methanol-d⁴) : d 8.64 (bs,

1 H, Ar) , 7.94 (d, J = 9.0 Hz, 1 H, Ar) , 7.82 (d, J = 7.0 Hz,

2 H, Ph) , 7.48 (t, J = 7.0 Hz, 1 H, Ph) , 7.43 (t, J = 7.0 Hz, 1 H, Ph) , 7.12 (d, J = 9.0 Hz, 1 H, Ar) , 4.20 (dd, J = 5.0, 9.0 Hz, 1 H, CHCH₂), 3.73 (dd, J^" = 5.0, 14.0 Hz, 1 H, CHCHH), 3.70-3.66 (m, superimposed, 7 H, NCH₂CH₂N, CH₂N(C=N)), 3.52 (t, J = 6.0 Hz, 2 H, CH₂NHAr) , 3.45 (dd, J = .0 , 14.0 Hz, 1 H, CHCHH); ¹³C NMR (125 MHz, methanol-d⁴): d 172.7, 168.3, 161.6, 148.0, 142.1, 135.8, 133.5, 132.9, 130.0, 128.0, 127.7, 122.3, 114.9, 56.7, 44.1, 43.2, 42.9, 42.7; FAB-HRMS (M+H^1") calcd 520.1614, found 520.1630.

Synthesis of compound 69 as illustrated in Figure 10. To a solution of the fluoride 57 (0.10 grams, 0.20 mmol) in dry DMF (10 mL) at room temperature a stream of NH_3(g) was bubbled through for 1 hour. After stirring for 4 hours, the reaction mixture was diluted with ethyl acetate and water. The layers were seperated and the organic layer was washed with water (2 x 10 mL) , brine (20 mL) and dried (Na₂S0₄) . The solvent was removed in vacuo to give 61 as a yellowish oil (0.09 grams, 93%). R_f - 0.25 (silica, 50% ethyl acetate in hexane) ; IR (thin film): n_max 3359, 1729, 1631, 1516, 1308, 1258, 1158, 1093 cm^"1; ^λE NMR (500 MHz, methanol-d⁴): d 8.54 (d, J = 2.0 Hz, 1 H, Ar) , 7.83-7.81 (m, 2 H, Ar) , 7.74 (dd, J = 2.0, 9.0 Hz, 1 H, Ar) , 7.52-7.43 (m, 3 H, Ar) , 6.97 (d, J^" = 9.0 Hz, 1 H, Ar) , 4.12 (dd, J = 6.0, 8.0 Hz, 1 H, CH) , 3.64 (dd, J = 6.0, 13.5 Hz, 1 H, CHH), 3.47 (dd, J = 8.0, 13.5 Hz, 1 H, CHH), 1.25 (s, 9 H, ^fcBu) ; ¹³C NMR (125 MHz, methanol-d⁴): d 170.5, 168.3, 149.4, 142.2, 134.8, 133.6, 131.7, 130.1, 128.1, 127.1, 122.2, 119.9, 83.4, 57.3, 43.2, 27.9; FAB-HRMS calcd (M+Cs⁺) 597.0420, found 597.0439.

Synthesis of compound 70 as illustrated in Figure 10. To a solution of amine 69 (0.23 grams, 0.50 mmol) in methanol (15 mL) at room temperature was added 10% Pd/C (0.10 g) under argon. The flask was then equipped with a balloon containing H_2(g) . After 8 hours, the reaction mixture was filtered through a pad of celite and the solvent removed in vacuo to give 70 as a brownish-reddish oil (0.19 grams, 90%) . R_f = 0.11 (silica, 80% ethyl acetate in hexane) ; IR (thin film): n^ 3360, 2979, 1729, 1625, 1582, 1542, 1508, 1447, 1369, 1310, 1248, 1160, 1093, 758, 721, 688, 590 cm¹; ^λE NMR (500 MHz, methanol-d⁴): d 7.82-7.80 (m, 2 H, Ar) , 7.53-7.49 (m, 1 H, Ar) , 7.46-7.43 (m, 2 H, Ar) , 7.11 (d, J = 2.0 Hz, 1 H, Ar) , 7.05 (d, J^" = 2.0 Hz, 1 H, Ar) , 6.64 (d, J = 8.5 Hz, 1 H, Ar) , 4.08 (dd, J =7.5, 14.5 Hz, 1 H, CH) , 3.61 (dd, J = 6.0, 13.5 Hz, 1 H, CHH), 3.47 (dd, J = 8.0, 13.5 Hz, 1 H, CHH), 1.22 (s, 9 H, 'B ); ¹³C NMR (125 MHz, methanol-d⁴): d 170.8, 170.6, 142.1, 141.2, 134.8, 133.7, 130.1, 128.1, 124.5, 120.6, 116.5, 115.5, 83.3, 57.5, 43.1, 28.0; FAB-HRMS calcd (M+Na⁺) 435.1702, found 434.1727.

Synthesis of compound 71 as illustrated in Figure 10. To a solution of the diamine 70 (0.092 grams, 0.20 mmol) in ethanol (20 mL) was added triethylamine (0.032 mL, 0.22 mmol) and phenyl isothiocyanate (0.028 mL, 0.22 mmol) . After 14 hours, the solvent was removed in vacuo to give a brown residue which was purified by preparative thin layer chromatography (silica, 5% methanol in dichloromethane) to give 71 as a brown solid (0.082 grams, 69%). R_f = 0.16 (silica, 5% methanol in dichloromethane) ; IR (thin film) : n_max 3316, 3061, 2978, 1729, 1624, 1504, 1448, 1368, 1309, 1252,

1159, 1092, 837, 733 cm^"1; ^XH NMR (500 MHz, CDC1₃) : d 8.15 (bs, 1 H, NH) , 7.81 (d, J = 7.5 Hz, 2 H, Ar) , 7.56-7.03 (m, 14 H) , 6.78 (bs, 1 H, NHC=0) , 6.58 (d, J = 8.0 Hz, 1 H, HNS0₂Ph) , 4.51 (bs, 1 H) , 4.05 (bs, 1 H) , 3.67 (bs, 1 H) , 1.20 (s, 9 H, ^fcBu) ; ^XE NMR (500 MHz, CDC1₃) : d 180.3, 168.6, 167.4, 147.0,

143.3, 139.6, 137.6, 132.7, 129.0, 128.4, 127.1, 126.6, 125.4, 123.5, 116.1, 83.2, 60.3, 56.5, 42.0, 27.5; FAB-HRMS calcd (M+Cs⁺) 702.0821, found 702.0797.

Synthesis of compound 72 as illustrated in Figure 10. To a solution of the thiourea 71 (0.077 grams, 0.14 mmol) in DMF (10 mL) at room temperature was added triethylamine (0.02 mL, 0.14 mmol) and mercury (II) chloride (0.04 grams, 0.14 mmol). After 4 hours, the reaction mixture was filtered through celite and rinsed with ethyl acetate. The solvent was removed in vacuo to give 72 as a brown residue (0.05 grams, 81%) which was carried onto the next step. R_f = 0.32 (silica, 5% methanol in dichloromethane); ^λE NMR (500 MHz, CDC1₃): d 7.98 (m, 2 H, Ar) , 7.53-6.90 (m, 15 H, Ar) , 4.16 (m, 1 H, CH) , 3.83 (bs, 1 H, CHH), 3.62 (bs, 1 H, CHH), 1.25 (bs, 9 H, 'Bu) ; FAB- HRMS calcd (M+Cs⁺) 668.0944, found 668.0923.

Synthesis of compound 22 as illustrated in Figure 10. Compound

22 was prepared by the same procedure as for 10 using 72 in lieu of 36b. Yield: (0.04 grams, 88%). R_t = 14.8 min; ^λE NMR (500 MHz, methanol-d⁴): d 7.85-7.82 (m, 3 H, Ar) , 7.75 (dd, J = 1.5, 8.5 Hz, 1 H, Ar) , 7.56-7.41 (m, 9 H, Ar) , 4.22 (dd, J = 5.0, 9.0 Hz, 1 H, CH) , 3.78 (dd, J = 5.0, 13.5 Hz, CHH), 3.48 (dd, J^" = 9.0, 13.5 Hz, CHH); ¹³C NMR (150 MHz, methanol-d⁴): d 171.9, 169.2, 150.7, 141.6, 136.2, 133.1, 131.2, 130.9, 130.6, 129.5, 128.3, 127.5, 124.6, 124.1, 111.9, 111.8, 56.1, 42.8; FAB-HRMS calcd (M+H⁺) 480.1342, found 480.1352.

Claims

What is claimed is:

1. An RGD mimetic represented by the following structure:

0

wherein R¹ is a radical selected from a group consisting of one of the following structures:

X is a diradical selected from a group consisting of sulfur, - NH- and oxygen; R² is a radical selected from a group consisting of -C0₂t-Butyl, -CO-Aryl and -S0₂-Aryl.

2. An RGD mimetic as described in claim 1 wherein Aryl is selected from a group consisting of phenyl, 1-naphthyl, and 2- naphthyl .

3. An RGD mimetic as described in claim 2 wherein R² is - S0₂-Aryl.

4. An RGD mimetic as described in claim 1 represented by the following structure:

5. An RGD mimetic as described in claim 1 represented by the following structure:

6. An RGD mimetic as described in claim 1 represented by the following structure:

7. An RGD mimetic as described in claim 1 represented by the following stru

8. An RGD mimetic as described in claim 1 represented by the following

9. An RGD mimetic as described in claim 1 represented by the following structure:

10. An RGD mimetic as described in claim 1 represented by the following structure:

11. An RGD mimetic as described in claim 1 represented by the following struct

12. An RGD mimetic as described in claim 1 represented by the following structure:

13. An RGD mimetic as described in claim 1 represented by the following struct

14. An RGD mimetic as described in claim 1 represented by the following structure:

15. An RGD mimetic as described in claim 1 represented by the following structure:

16. A method for producing an RGD mimetic represented by the following structure:

X is a diradical selected from a group consisting of sulfur, NH- and oxygen; R² is a radical selected from a group consisting of -C0₂t-Butyl, -CO-Aryl and -S0₂-Aryl;

the method comprising the following steps:

Step 1: Providing a nitroaryl precursor having a fluoride group covalently attached to the nitroaryl ring represented by the following structure: o

wherein R₃ is an acid protecting group; then

Step 2: Displacing the fluoride group with a nucleophile having a protected guanidine group using nucleophilic aromatic substitution for producing a protected RGD mimetic; and then Step 3 : Deprotecting the protected RGD mimetic with an acid for producing the RDG mimetic.

17. An RGD mimetic represented by the following structure:

wherein R² is a radical selected from a group consisting of -C0₂t-Butyl, and -S0₂-Aryl.

18. An RGD mimetic as described in claim 17 wherein Aryl is selected from a group consisting of phenyl, 1-naphthyl, and 2- naphthyl.

19. A process for differentially inhibiting ╬▒_iib╬▓₃ mediated cell adhesion over _v╬▓₃ mediated cell adhesion comprising the following step:

contacting ╬▒_iib╬▓₃ expressing cells with a solution containing an RGD mimetic selected from the compounds of claims 5, 7, 9, 11, 14, or 15, said solution having a concentration of the RGD mimetic sufficient for inhibiting ╬▒_iib╬▓₃ mediated cell adhesion,

wherein ╬▒_iib╬▓₃ mediated cell adhesion is inhibited at least approximately 100 fold more than ╬▒_v╬▓₃ mediated cell adhesion.